Search

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

OBJECTIVES/GOALS: This study seeks to elucidate the relationships between early life adversity (ELA), social learning, and empathic responding. Specifically, it aims to understand the impact of ELA on the expression of empathy and ability to adjust behavior after social observation. METHODS/STUDY POPULATION: 60 healthy participants ages 18-65 will be recruited from the greater Baltimore area. They will undergo a placebo manipulation paradigm with simultaneous EEG recording to capture neural oscillations in frontal and insular cortices and event-related potentials. Participants will observe a demonstrator who indicates pain relief in response to the application of an inert cream. Then, while undergoing heat pain stimulations, the participant will receive the same inert cream and rate their physiological and psychological pain experience using a visual analog scale. The heat stimulations will be lowered without their knowledge to measure placebo response. Participants will also answer a battery of questionnaires which assess personality, psychological factors, life history, empathy, and current social life. RESULTS/ANTICIPATED RESULTS: It is expected that ELA will result in decreased placebo response, interpreted as deficits in social learning. Further, we expect that this effect is moderated by state empathy, empathy in a specific context or moment. We predict that individuals with lower state empathy and exposure to adversity will have greater deficits in social learning. We also expect to see more robust event-related potentials preceding painful stimulations at electrodes corresponding to the medial and ventral prefrontal cortex and insula in ELA-exposed participants. Because these brain regions are connected to anticipatory and predictive circuits, this would indicate that the individual has not adjusted their expectations according to the social information gained via observation. DISCUSSION/SIGNIFICANCE: Results of this study will expand our understanding of how ELA impacts behavior throughout life. Individuals with a history of ELA often face social difficulties and a higher risk of psychiatric disorders. This study will illuminate possible neural correlates of these differences in social behavior and, more generally, the expression of empathy.

The explosive pace of development and research in medical extended reality (MXR) is a testament to its promise for health care and medicine. In comparison with this growth, there is a relative sparsity of rigorous clinical trials that establish the efficacy and effectiveness of these interventions. Explicating mechanisms of action across clinical areas and MXR applications is another major area of need. A primary impediment to these goals is a lack of frameworks for trial design, more specifically, the selection of appropriate controls that effectively address unique elements of MXR. This paper delineates a framework for designing controls, sham conditions, and comparators, as well as proposed considerations for MXR trial designs. Special consideration is given to the design of sham conditions. Improved designs would enable more robust findings and the development of generalizable knowledge that could be adopted across MXR interventions.

Abstract The placebo effect demonstrates how positive expectancies shape the effectiveness of various treatments. Across studies, placebo treatments are interventions (creams, pills, etc.) that are presented to individuals as, and are learned to be, beneficial for them. This study tested whether placebo-induced expectancies can be harnessed to improve individuals’ internal emotion regulation attempts. Participants implemented two types of distraction, an emotion regulation strategy involving attentional disengagement, to attenuate fear of pain. In a typical conditioning paradigm, the placebo-distraction was introduced as an effective strategy (verbal suggestion) and was surreptitiously paired with reduced pain (conditioning), whereas the control-distraction was introduced as noneffective and was surreptitiously paired with increased pain. As predicted, we found that during a later test phase, where pain intensity was identical, the placebo-distraction resulted in reduced self-reported fear of pain, relative to the control-distraction. Moreover, we utilized a robust behavioral choice measure, demonstrating increased preferences for the placebo-distraction. We additionally tested whether these effects generalize to a different emotional context of fear of unpleasant pictures. In that context, the placebo-distraction was as effective as the control-distraction, but was substantially preferred. This study demonstrates that the placebo effect can be expanded to include individuals’ internal attempts to influence their conditions.

ObjectiveEmerging 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.DesignThe 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.SettingInternational.Main outcome measuresThe 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.ParticipantsThe 10 international vNGT participants had a variety of clinical backgrounds and research specializations and were all specialists in contextual factors research.ResultsA 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.ConclusionOur 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.

Introduction Patients with head and neck cancer have a substantial risk of chronic opioid dependence following surgery due to pain and psychosocial consequences from both the disease process and its treatments. Conditioned open-label placebos (COLPs) have been effective for reducing the dose of active medication required for a clinical response across a wide range of medical conditions. We hypothesise that the addition of COLPs to standard multimodal analgesia will be associated with reduced baseline opioid consumption by 5 days after surgery in comparison to standard multimodal analgesia alone in patients with head and neck cancer.Methods and analysis This randomised controlled trial will evaluate the use of COLP for adjunctive pain management in patients with head and neck cancer. Participants will be randomised with 1:1 allocation to either the treatment as usual or COLP group. All participants will receive standard multimodal analgesia, including opioids. The COLP group will additionally receive conditioning (ie, exposure to a clove oil scent) paired with active and placebo opioids for 5 days. Participants will complete surveys on pain, opioid consumption and depression symptoms through 6 months after surgery. Average change in baseline opioid consumption by postoperative day 5 and average pain levels and opioid consumption through 6 months will be compared between groups.Ethics and dissemination There remains a demand for more effective and safer strategies for postoperative pain management in patients with head and neck cancer as chronic opioid dependence has been associated with decreased survival in this patient population. Results from this study may lay the groundwork for further investigation of COLPs as a strategy for adjunctive pain management in patients with head and neck cancer. This clinical trial has been approved by the Johns Hopkins University Institutional Review Board (IRB00276225) and is registered on the National Institutes of Health Clinical Trials Database.Trial registration number NCT04973748.

Chronic pain is the leading cause of disability among United States veterans. Affecting up to 70% of veterans, chronic pain touches all aspects of life, not just physical functioning. Despite the fact that the nation is experiencing a crisis with substance use disorder, the most common treatment for pain among veterans is opioids. The purpose of this community engagement project was to develop a national veteran-centered chronic pain research agenda. In total, 129 veterans and stakeholders engaged in Think Tank Meetings across five states: Florida, Georgia, Illinois, North Carolina, and Virginia. Veterans revealed they wanted better access to care, better care coordination, and more options for managing chronic pain. Veterans’ recommendations for chronic pain management and veteran-generated priorities for chronic pain research are presented. The outcomes of this community engagement project can be used by researchers, clinicians, health care providers, health care system managers, and policy-makers to engage in activities that are veteran-centered and veteran-driven.

Abstract. Adverse childhood experiences (ACEs) affect over half of the adults in the United States and are known to contribute to the development of a wide variety of negative health and behavioral outcomes. The consequences of ACE exposure have been studied in patient populations that include individuals with gynecologic, orthopedic, metabolic, autoimmune, cardiovascular, and gastrointestinal conditions among others. Findings indicate that ACEs not only increase risks for chronic pain but also influence emotional responses to pain in many of these individuals. A growing body of research suggests that these effects may be the result of long-lasting changes induced by ACEs in neurobiological systems during early development. However, one area that is still largely unexplored concerns the effects of ACEs on burn patients, who account for almost 450,000 hospitalizations in the United States annually. Patients with severe burns frequently suffer from persistent pain that affects their well-being long after the acute injury, but considerable variability has been observed in the experience of pain across individuals. A literature search was conducted in CINAHL and PubMed to evaluate the possibility that previously documented ACE-induced changes in biological, psychological, and social processes might contribute to these differences. Findings suggest that better understanding of the role that ACEs play in burn outcomes could lead to improved treatment strategies, but further empirical research is needed to identify the predictors and mechanisms that dictate individual differences in pain outcomes in patients with ACE exposure and to clarify the role that ACE-related alterations play in early healing and recovery from burn injuries.

BackgroundThe Society of Interdisciplinary Placebo Studies (SIPS) was one of many organizations that hosted a virtual scientific conference in response to the COVID-19 pandemic restrictions. Retaining essential benefits of an in-person conference experience was a primary objective for the SIPS conference planning committee and guided the selection of a virtual platform on which to host the 2021 meeting. This article reports on the methods used to design and analyze an engaging, virtual scientific conference, along with the findings and implications for future meetings.MethodsParticipant use of and interaction with different features of the conference platform were recorded and exported for analysis. Additionally, all SIPS conference attendees were invited to complete a brief, online post-conference survey that inquired about their perceptions of the SIPS conference specifically as well as their opinions of virtual and hybrid conferences in general. Using these data, we assessed (1) attendance patterns, (2) level of engagement, and (3) attendee satisfaction.ResultsThe platform recorded 438 unique, active conference attendees who used either a mobile app, web browser, or both to participate during the 3-day program. Seventy-four percent (N = 324) of active users attended all 3 days with 30 and 26 new attendees on Days 2 and 3, respectively. The connections feature offered on the platform was the most utilized function within the online forum. Attendance in the parallel workshop sessions remained constant across the 3 days, with an average of 44.6% (SD = 6.77) of people moving between workshops within a single session. The two poster sessions had an average of 47.6 (SD = 17.97) and 27.8 (SD = 10.24) unique views per poster, respectively. Eleven percent (N = 48) of attendees completed the post-conference survey. Thirty-six percent of these responders stated they were only able to attend because the conference was offered virtually. Further, the quality of the conference had an average satisfaction rating of 68.08 out of 100 (SD = 22.94).ConclusionResults of data analyses suggest the virtual platform allowed for those who were unable to attend to join virtually, produced moderate engagement throughout the conference, and that the majority of attendees were satisfied with the quality of the fully-virtual conference. Therefore, incorporating virtual aspects in future in-person conferences could enhance conference experience and participation.

ObjectiveDespite years of research and the development of countless awareness campaigns, the number of deaths related to prescription opioid overdose is steadily rising. Often, naive patients undergoing trauma-related surgery are dispensed opioids while in the hospital, resulting in an escalation to long-term opioid misuses. We explored the impact of an educational intervention to modify perceptions of opioid needs at the bedside of trauma inpatients in post-surgery pain management.Materials and MethodsTwenty-eight inpatients with acute post-surgical pain completed this proof-of-concept study adopting an educational intervention related to opioids and non-pharmacological strategies in the context of acute post-surgical pain. An education assessment survey was developed to measure pre- and post-education perceptions of opioid needs to manage pain. The survey statements encompassed the patient’s perceived needs for opioids and other pharmacological and non-pharmacological therapeutics to manage acute pain. The primary outcome was the change in the patient’s perceived need for opioids. The secondary (explorative) outcome was the change in Morphine Milligram Equivalents (MME) used on the day of the educational intervention while inpatients and prescribed at the time of the hospital discharge.ResultsAfter the educational intervention, patients reported less agreement with the statement, “I think a short course of opioids (less than 5 days) is safe.” Moreover, less agreement on using opioids to manage trauma-related pain was positively associated with a significant reduction in opioids prescribed at discharge after the educational intervention. The educational intervention might have effectively helped to cope with acute trauma-related pain while adjusting potential unrealistic expectancies about pain management and, more in general, opioid-related needs.ConclusionThese findings suggest that trauma patients’ expectations and understanding of the risks associated with the long-term use of opioids can be modified by a short educational intervention delivered by health providers during the hospitalization. Establishing realistic expectations in managing acute traumatic pain may empower patients with the necessary knowledge to minimize the potential of continuous long-term opioid use, opioid misuse, and the development of post-trauma opioid abuse and/or addiction.

Abstract 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).

Standard opioid tapers tend to be associated with increased patient anxiety and higher pain ratings. Pre-authorized concealed opioid reductions may minimize expectations such as fear of increased pain due to the reduction of opioids and, prolong analgesic benefits in experimental settings. We recently observed that patients and clinicians are open to concealed opioid tapering. However, little is known about the “why” behind their attitudes. Based on this lack of data, we analyzed qualitative responses to survey questions on patients' and clinicians' acceptance of a concealed opioid reduction for chronic pain. Seventy-four patients with a history of high dose opioid therapy and 49 clinicians completed a web-based questionnaire with open-ended questions examining responses to two hypothetical clinical trials comparing a concealed opioid reduction pre-authorized by patients vs. standard tapering. We used content analysis based on qualitative descriptive methodology to analyze comments from the patients and clinicians. Five themes were identified: informed consent; anxiety; safety; support; and ignorance is bliss, or not. These themes highlight the overall positive attitudes toward concealed opioid tapers. Our findings reinforce the importance of patient-centered care and are expected to inform the design of clinical trials from both the patient and clinician perspective. This qualitative study presents patients' and clinicians' attitudes toward hypothetical scenarios for a trial of pre-authorized reduction of opioids. The findings indicate positive attitudes and the relevance of engaging patients with effective decision-making processes.

Chronic pain imposes a significant burden to the healthcare system and adversely affects patients' quality of life. Traditional subjective assessments, however, do not adequately capture the complex phenomenon of pain, which is influenced by a multitude of factors including environmental, developmental, genetic, and psychological. Quantitative sensory testing (QST), established as a protocol to examine thermal and mechanical sensory function, offers insight on potential mechanisms contributing to an individual's experience of pain, by assessing their perceived response to standardized delivery of stimuli. Although the use of QST as a research methodology has been described in the literature in reference to specific pain populations, this manuscript details application of QST across a variety of chronic pain conditions. Specific conditions include lower extremity chronic pain, knee osteoarthritis, chronic low back pain, temporomandibular joint disorder, and irritable bowel syndrome. Furthermore, we describe the use of QST in placebo/nocebo research, and discuss the use of QST in vulnerable populations such as those with dementia. We illustrate how the evaluation of peripheral sensory nerve function holds clinical promise in targeting interventions, and how using QST can enhance patient education regarding prognostic outcomes with particular treatments. Incorporation of QST methodology in research investigations may facilitate the identification of common mechanisms underlying chronic pain conditions, guide the development of non-pharmacological behavioral interventions to reduce pain and pain-related morbidity, and enhance our efforts toward reducing the burden of chronic pain.

Introduction: Virtual reality (VR) has the potential to lessen pain and anxiety experienced by pediatric patients undergoing burn wound care procedures. Population-specific variables require novel technological application and thus, a systematic review among studies on its impact is warranted.Objective: The objective of this review was to evaluate the effectiveness of VR on pain in children with burn injuries undergoing wound care procedures.Methods: A systematic literature review was performed using PubMed and CINAHL databases from January 2010 to July 2021 with the keywords “pediatric,” “burn,” “virtual reality,” and “pain.” We included experimental studies of between- and within-subjects designs in which pediatric patients’ exposure to virtual reality technology during burn wound care functioned as the intervention of interest. Two researchers independently performed the literature search, made judgements of inclusion/exclusion based on agreed-upon criteria, abstracted data, and assessed quality of evidence using a standardized appraisal tool. A meta-analysis was conducted to evaluate the effectiveness of the VR on burning procedural pain in pediatric population. Standardized mean difference (SMD) was used as an index of combined effect size, and a random effect model was used for meta-analysis.Results: Ten articles published between January 2010 and July 2021 passed the selection criteria: six randomized controlled trials and four randomized repeated-measures studies. Consistent results among the studies provided support for VR as effective in reducing pain and potentially pain related anxiety in children undergoing burn wound care through preprocedural preparation (n = 2) and procedural intervention (n = 8). A random effects meta-analysis model indicated a moderate and significant combined effect size (SMD = 0.60, 95% CI = 0.28–0.93, p = 0.0031) of VR effects on pain intensity ratings with no significant heterogeneity of VR intervention effects between studies. Only one study reported direct influence of VR intervention on pre-procedural situational anxiety with a moderate effect size (Cohen’s d = 0.575, 95%CI = 0.11–1.04).Conclusion: Children’s exposure to VR during burn care procedures was associated with lower levels of pain and pain related anxiety. Moderate to large effect sizes support the integration of VR into traditional pediatric burn pain protocols irrespective of innovative delivery methods and content required for use in burned pediatric patients.

Introduction The annual mortality and national expense of the opioid crisis continue to rise in the USA (130 deaths/day, $50 billion/year). Opioid use disorder usually starts with the prescription of opioids for a medical condition. Its risk is associated with greater pain intensity and coping strategies characterised by pain catastrophising. Non-pharmacological analgesics in the hospital setting are critical to abate the opioid epidemic. One promising intervention is virtual reality (VR) therapy. It has performed well as a distraction tool and pain modifier during medical procedures; however, little is known about VR in the acute pain setting following traumatic injury. Furthermore, no studies have investigated VR in the setting of traumatic brain injury (TBI). This study aims to establish the safety and effect of VR therapy in the inpatient setting for acute traumatic injuries, including TBI.Methods and analysis In this randomised within-subjects clinical study, immersive VR therapy will be compared with two controls in patients with traumatic injury, including TBI. Affective measures including pain catastrophising, trait anxiety and depression will be captured prior to beginning sessions. Before and after each session, we will capture pain intensity and unpleasantness, additional affective measures and physiological measures associated with pain response, such as heart rate and variability, pupillometry and respiratory rate. The primary outcome is the change in pain intensity of the VR session compared with controls.Ethics and dissemination Dissemination of this protocol will allow researchers and funding bodies to stay abreast in their fields through exposure to research not otherwise widely publicised. Study protocols are compliant with federal regulation and University of Maryland Baltimore’s Human Research Protections and Institutional Review Board (protocol number HP-00090603). Study results will be published on completion of enrolment and analysis, and deidentified data can be shared by request to the corresponding author.Trial registration number NCT04356963; Pre-results.

OBJECTIVES/GOALS: Pain Catastrophizing is a negative coping mechanism involving rumination, magnification, and helplessness and is associated with worse chronic pain. The neurobiological mechanisms underlying this relationship are poorly understood. We aim to examine the intrinsic activity of a functional pathway in patients with chronic orofacial pain. METHODS/STUDY POPULATION: This is the second phase of a parent study examining genetics, placebos, and the brain in temporomandibular disorders (TMD). We intend to recruit 120 of the original 398 TMD patients for this phase. Participants completed the Graded Chronic Pain Scale to assess TMD pain intensity and disability and the Pain Catastrophizing Scale. Behaviorally, pain catastrophizing scores and pain intensity and disability will be analyzed using structural equation modeling. Resting-state functional magnetic resonance imaging will be used to record intrinsic brain activity. The functional connectivity between the posterior cingulate, anterior insula, and periaqueductal grey will be assessed as a causal pathway relating pain catastrophizing to pain intensity and disability. Mediation analyses will be used to test causality. RESULTS/ANTICIPATED RESULTS: We anticipate that greater engagement in catastrophic thinking about pain increases the functional connectivity strength between the posterior cingulate, anterior insula, and periaqueductal grey, which ultimately leads to heightened perception of pain intensity and disability. Therefore, we expect to see increased functional connectivity in those with high pain catastrophizing levels as compared to those with low pain catastrophizing levels, and that this pathway will mediate the relationship between pain catastrophizing and pain intensity and disability. Further, we predict that helplessness will most strongly correlate with the change in functional connectivity as compared to rumination and magnification. Results will be presented in full at the conference. DISCUSSION/SIGNIFICANCE: Understanding how pain catastrophizing can influence chronic pain pathways will not only promote a more integrative approach to chronic pain management but will also help identify the mechanisms by which pain itself develops and persists in the particularly vulnerable pain population of TMD.

ABSTRACT. Introduction:. The unknown and uncontrollable situation of the coronavirus disease 2019 (COVID-19) pandemic may have triggered changes in pain, anxiety, and depression along with a perception of nonspecific COVID-19 symptoms. Objectives:. We determined how anxiety, depression, and pain outcomes varied during the “Stay-at-Home” order compared with the prepandemic period and whether nonspecific COVID-19 symptoms would occur. Methods:. We conducted an online survey to opportunistically reassess clinical anxiety, depression, pain intensity, and pain interference while controlling for somatic symptom severity during the prepandemic and Stay-at-Home order period. During the Stay-at-Home period, anxiety, depression, pain intensity, and pain interference were reassessed. Coping strategies were assessed as a critical factor influencing pain behaviors. In addition, we explored the occurrence of nonspecific COVID-19 symptoms with an ad hoc survey referencing the Centers for Disease Control and Prevention publicly available COVID-19 symptoms. Results:. We observed a significant increase in depression and anxiety levels during the Stay-at-Home period. Coping strategy changes (eg, increased exercise) were linked to lower pain severity and interference which improved overall. Participants who self-reported nonspecific COVID-19 symptoms had higher prepandemic depression. Among the 72 participants not diagnosed with COVID-19, 70.8% of the participants experienced symptoms resembling those associated with COVID-19. Conclusion:. We suggest the parallel between pain outcome improvement and worsening anxiety and depression during the Stay-at-Home order might reflect a shift in symptoms, indicating that those patients with underlying mood disorders may require more help than they did before the pandemic.

ObjectiveThe aim of this study was to investigate the knowledge of orthopedic manual therapists (OMTs) regarding context factors (CFs) capable of triggering nocebo effects during the treatment and how this knowledge is related to their socio-demographic features.DesignA cross-sectional online survey.SettingNational.Main Outcome MeasuresA 20 items questionnaire composed by open-ended and closed single-choice questions was administered to explore: (a) socio-demographic variables (10 questions); (b) the relation between different CFs and nocebo-related effects (2 questions); and (c) the knowledge of participants about nocebo-related effects and how they managed them in the clinical practice (8 questions).Participants1288 OMTs were recruited from the database of the Master in Rehabilitation of Musculoskeletal Disorders (MRDM) of the University of Genova from March to May 2019. Inclusion criteria were: (a) to possess a valid email account; (b) to understand and use as a native language the Italian; (c) to be graduated as OMTs; and (d) to be employed as physiotherapists specialized-OMTs during the survey.Results791 responses were received (61.4%); 473 of them were male (59.8%), with an average age of 31.0 ± 7.1 years. OMTs defined nocebo-related effects as the psychosocial context effects around therapy and patient with specific biological bases (72.2%). OMTs know that their clinical practice is pervaded by nocebo-related effects (42.5%), triggered by CFs. Participants communicated nocebo-related effects balancing the positive features of the therapy with the negative ones (50.9%), during the decision of the therapeutic plan (42.7%). They reported associative learning as the main mechanism involved in nocebo-related effects (28.8%). OMTs taught and trained patient’s strategies to manage nocebo-related effects (39.6%) through an evaluation and correction of patient’s anxieties, doubts and expectations (37.7%). OMTs most frequently considered themselves to have a “medium” education about nocebo-related effects (48.2%) and that their management should be taught during bachelor (78.6%).ConclusionOMTs believed that nocebo-related effects were present in their clinical practice and that they can be triggered by CFs.

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.

Successfully predicting the susceptibility of individuals to placebo analgesics will aid in developing more effective pain medication and therapies, as well as aiding potential future clinical use of placebos. In pursuit of this goal, we analyzed healthy and chronic pain patients' patterns of responsiveness during conditioning rounds and their links to conditioned placebo analgesia and the mediating effect of expectation on those responses. We recruited 579 participants (380 healthy, 199 with temporomandibular disorder [TMD]) to participate in a laboratory placebo experiment. Individual pain sensitivity dictated the temperatures used for high- and low-pain stimuli, paired with red or green screens, respectively, and participants were told there would be an analgesic intervention paired with the green screens. Over two conditioning sessions and one testing session, participants rated the painfulness of each stimulus on a visual analogue scale from 0 to 100. During the testing phase, the same temperature was used for both red and green screens to assess responses to the placebo effect, which was defined as the difference between the average of the high-pain-cue stimuli and low-pain-cue stimuli. Delta scores, defined as each low-pain rating subtracted from its corresponding high-pain rating, served as a means of modeling patterns of conditioning strength and placebo responsiveness. Latent class analysis (LCA) was then conducted to classify the participants based on the trajectories of the delta values during the conditioning rounds. Classes characterized by persistently greater or increasing delta scores during conditioning displayed greater placebo analgesia during testing than those with persistently lower or decreasing delta scores. Furthermore, the identified groups' expectation of pain relief acted as a mediator for individual placebo analgesic effects. This study is the first to use LCA to discern the relationship between patterns of learning and the resultant placebo analgesia in chronic pain patients. In clinical settings, this knowledge can be used to enhance clinical pain outcomes, as chronic pain patients with greater prior experiences of pain reduction may benefit more from placebo analgesia.

Introduction Physicians and other prescribing clinicians use opioids as the primary method of pain management after traumatic injury, despite growing recognition of the major risks associated with usage for chronic pain. Placebos given after repeated administration of active treatments can acquire medication-like effects based on learning mechanisms. This study hypothesises that dose-extending placebos can be an effective treatment in relieving clinical acute pain in trauma patients who take opioids.Methods and analysis The relieving acute pain is a proof-of-concept randomised, placebo-controlled, double-blinded, single-site study enrolling 159 participants aged from 18 to 65 years with one or more traumatic injuries treated with opioids. Participants will be randomly assigned to three different arms. Arm 1 will receive the full dose of opioids with non-steroidal anti-inflammatory drugs (NSAIDs). Arm 2 will receive the 50% overall reduction in opioid dosage, dose-extending placebos and NSAIDs. Arm 3 (control) will receive NSAIDs and placebos. The trial length will be 3 days of hospitalisation (phase I) and 2-week, 1-month, 3-month and 6-month follow-ups (exploratory phase II). Primary and secondary outcomes include feasibility and acceptability of the study. Pain intensity, functional pain, emotional distress, rates of rescue therapy requests and patient-initiated medication denials will be collected.Ethics and dissemination All activities associated with this protocol are conducted in full compliance with the Institutional Review Board policies and federal regulations. Publishing this study protocol will enable researchers and funding bodies to stay up to date in their fields by providing exposure to research activity that may not otherwise be widely publicised.Date and protocol version identifier 3/6/2019 (HP-00078742).Trial registration number NCT03426137.

Nocebo effects encompass negative responses to inert interventions in the research setting and negative outcomes with active treatments in the clinical research or practice settings, including new or worsening symptoms and adverse events, stemming from patients’ negative expectations and not the pharmacologic action of the treatment itself. Numerous personality, psychosocial, neurobiological, and contextual/environmental factors contribute to the development of nocebo effects, which can impair quality of life and reduce adherence to treatment. Biologics are effective agents widely used in autoimmune disease, but their high cost may limit access for patients. Biosimilar products have gained regulatory approval based on quality, safety, and efficacy comparable to that of originator biologics in rigorous study programs. In this review, we identified gaps in patients’ and healthcare professionals’ awareness, understanding, and perceptions of biosimilars that may result in negative expectations and nocebo effects, and may diminish their acceptance and clinical benefits. We also examined features of nocebo effects with biosimilar treatment that inform research and clinical practices. Namely, when biosimilars are introduced to patients as possible treatment options, we recommend adoption of nocebo-reducing strategies to avoid negative expectations, including delivery of balanced information on risk–benefit profiles, framing information to focus on positive attributes, and promoting shared decision-making processes along with patient empowerment. Healthcare professionals confident in their knowledge of biosimilars and aware of bias-inducing factors may help reduce the risk of nocebo effects and improve patients’ adherence in proposing biosimilars as treatment for autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease.

Abstract. Introduction:. Research on learning in placebo and nocebo has relied predominantly on Pavlovian conditioning procedures. Operant learning procedures may more accurately model learning in real-life situations in which placebo and nocebo effects occur. Objectives:. To investigate the development and persistence of placebo and nocebo effects using an operant avoidance learning task. Methods:. Pain-free participants (n = 58) could learn to avoid pain by performing movements that differed in difficulty and intensity of painful stimulation. Participants performed movements in 2 contexts. In the high cost of avoidance context, pain stimulus intensity reduced with increasing movement difficulty. In the low cost of avoidance context, contingencies were reversed. Participants rated pain expectations and pain intensity. During test, movement difficulties were unchanged, but participants always received a medium-intensity pain stimulus. Placebo and nocebo effects were defined as lower/higher pain intensity ratings for trajectories that previously resulted in low/high-intensity compared with medium-intensity stimulation. Results:. As expected, participants acquired differential movement-pain expectations and differential movement choices. Testing with a medium-intensity pain stimulus quickly erased differences in movement choice across contexts, but differences in pain expectations were maintained. Pain modulation across context was in line with movement-pain expectations. However, we only observed placebo effects within the low cost of avoidance context and found no evidence of nocebo effects. Conclusion:. Operant learning can change pain expectations, pain modulation, and pain-related avoidance behavior. Persisting pain expectations suggest that acquired pain beliefs may be resistant to disconfirmation, despite self-initiated experience with novel pain-movement contingencies.

Abstract. Introduction:. Placebo and nocebo effects represent one of the most fascinating topics in the health care field. Objectives:. the aims of this discussion paper were (1) to briefly introduce the placebo and nocebo effects, (2) to elucidate the contextual factors able to trigger placebo and nocebo effects in the nursing field, and (3) to debate the impact of contextual factors on nursing education, practice, organisation, and research. Methods:. a narrative review was conducted based on the available evidence. Results:. Placebo responses (from Latin “I shall please”) are a beneficial outcome(s) triggered by a positive context. The opposite are the nocebo effects (from Latin “I shall harm”), which indicates an undesirable outcome(s) caused by a negative context. Both are complex and distinct psychoneurobiological phenomena in which behavioural and neurophysiological changes arise subsequent to an interaction between the patient and the health care context. Conclusion:. Placebo and nocebo concepts have been recently introduced in the nursing discipline, generating a wide debate on ethical issues; however, the impact on nursing education, clinical practice, nursing administration, and research regarding contextual factors triggering nocebo and placebo effects has not been debated to date.

Although critical for informed consent, side effect warnings can contribute directly to poorer patient outcomes because they often induce negative expectations that trigger nocebo side effects. Communication strategies that reduce the development of nocebo side effects whilst maintaining informed consent are therefore of considerable interest. We reviewed theoretical and empirical evidence for the use of framing strategies to achieve this. Framing refers to the way in which information about the likelihood or significance of side effects is presented (e.g., negative frame: 30% will experience headache vs. positive frame: 70% will not experience headache), with the rationale that positively framing such information could diminish nocebo side effects. Relatively few empirical studies (k = 6) have tested whether framing strategies can reduce nocebo side effects. Of these, four used attribute framing and two message framing. All but one of the studies found a significant framing effect on at least one aspect of side effects (e.g., experience, attribution, threat), suggesting that framing is a promising strategy for reducing nocebo effects. However, our review also revealed some important open questions regarding these types of framing effects, including, the best method of communicating side effects (written, oral, pictorial), optimal statistical presentation (e.g., frequencies vs. percentages), whether framing affects perceived absolute risk of side effects, and what psychological mechanisms underlie framing effects. Future research that addresses these open questions will be vital for understanding the circumstances in which framing are most likely to be effective.

The mechanisms underlying the transition from acute to chronic pain remain unclear. Here, we sought to characterize the transcriptome associated with chronic low back pain as well as the transcriptome of the transition from acute to chronic low back pain. For the analysis, we compared the whole blood transcriptome of: (a) patients at the onset of low back pain who no longer had pain within 6 weeks after onset (acute) with patients who developed chronic low back pain at 6 months (chronic T5); and, (b) patients at the onset of low back pain (chronic T1) who developed chronic pain at 6 months with healthy pain-free (normal) controls. The majority of differentially expressed genes were protein coding. We illustrate a unique chronic low back pain transcriptome characterized by significant enrichment for known pain genes, extracellular matrix genes, and genes from the extended major histocompatibility complex (MHC) genomic locus. The transcriptome of the transition from acute to chronic low back pain was characterized by significant upregulation of antigen presentation pathway (MHC class I and II) genes and downregulation of mitochondrial genes associated with oxidative phosphorylation, suggesting a unique genomic signature of vulnerability to low back pain chronicity.

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

Anxiety disorders impose substantial costs upon public health and productivity in the USA and worldwide. At present, these conditions are quantified by self-report questionnaires that only apply to behaviors that are accessible to consciousness, or by the timing of responses to fear- and anxiety-related words that are indirect since they do not produce fear, e.g., Dot Probe Test and emotional Stroop. We now review the conditioned responses (CRs) to fear produced by a neutral stimulus (conditioned stimulus CS+) when it cues a painful laser unconditioned stimulus (US). These CRs include autonomic (Skin Conductance Response) and ratings of the CS+ unpleasantness, ability to command attention, and the recognition of the association of CS+ with US (expectancy). These CRs are directly related to fear, and some measure behaviors that are minimally accessible to consciousness e.g., economic scales. Fear-related CRs include non-phase-locked phase changes in oscillatory EEG power defined by frequency and time post-stimulus over baseline, and changes in phase-locked visual and laser evoked responses both of which include late potentials reflecting attention or expectancy, like the P300, or contingent negative variation. Increases (ERS) and decreases (ERD) in oscillatory power post-stimulus may be generalizable given their consistency across healthy subjects. ERS and ERD are related to the ratings above as well as to anxious personalities and clinical anxiety and can resolve activity over short time intervals like those for some moods and emotions. These results could be incorporated into an objective instrumented test that measures EEG and CRs of autonomic activity and psychological ratings related to conditioned fear, some of which are subliminal. As in the case of instrumented tests of vigilance, these results could be useful for the direct, objective measurement of multiple aspects of the risk, diagnosis, and monitoring of therapies for anxiety disorders and anxious personalities.

BackgroundContextual factors (CFs) represent a potential therapeutic tool to boost physiotherapy outcomes, triggering placebo effects. Nevertheless, no evidence about the use of CFs among physical therapists is currently available.ObjectiveTo investigate the use of CFs and the opinion of Italian physical therapists specialized in Orthopaedic Manual Therapy (OMTs) on their therapeutic benefits.DesignAn exploratory cross-sectional online survey.MethodsA 17-item questionnaire and 2 clinical vignettes assessed the perspective of OMTs on the adoption of CFs in daily clinical practice. The target population was composed of 906 OMTs. An online survey was performed in 2016 using SurveyMonkey Software. Data were analyzed by descriptive and inferential statistics.ResultsA total of 558 volunteers (61.6% of the target OMT population) participated in the study. Half of the participants (52.0%) claimed to use CFs frequently in their practice. More of 50% of OMTs valued the therapeutic significance of CFs for different health problems as determined by a combined psychological and physiological effect. OMTs considered the use of CFs ethically acceptable when they exert beneficial therapeutic effects and their effectiveness has emerged in previous clinical experiences (30.6%). They disagreed on the adoption of CFs when they are deceptive (14.1%). Moreover, OMTs did not communicate the adoption of CFs to patients (38.2%), and CFs were usually used in addition to other interventions to optimize clinical responses (19.9%). Psychological mechanisms, patient's expectation and conditioning were believed to be the main components behind CFs (7.9%).LimitationsConsidering that the data collected were self-reported and retrospective, recall and response biases may limit the internal and external validity of the findings.ConclusionsOMTs used CFs in their clinical practice and believed in their therapeutic effect. The knowledge of CFs, placebo and nocebo mechanisms and their clinical effects should be included in physical therapists' university studies.

Abstract. Introduction:. Patient information leaflets on pain medication primarily list side effects while positive effects and action mechanisms remain underrepresented. Nocebo research has shown that negative instructions can lower analgesic effects. Objectives:. Research on information leaflets and their influence on mood, memory of side effects, and intake behavior of healthy participants is needed. Methods:. To determine the ratio of positive to negative phrases, 18 information leaflets of common, over-the-market analgesics were examined of which 1 was selected. In a randomized, controlled study design, 18 healthy participants read this leaflet while 18 control group participants read a matched, neutral leaflet of an electrical device. Collected data concerned the recall of positive and negative contents, mood, anxiety, and the willingness to buy and take the drug. Results:. All examined leaflets listed significantly more side effects than positive effects (t17 = 5.82, P < 0.01). After reading the analgesic leaflet, participants showed a trend towards more negative mood (F1,34 = 3.78, P = 0.06, ηp2 = 0.1), a lower intention to buy [χ2 (1, n = 36) = 12.5, P < 0.01], a higher unwillingness to take the medication [χ2 (1, n = 36) = 7.2, P < 0.01], and even a greater recall for side effects than positive effects (t17 = 7.47, P < 0.01). Conclusion:. Reading the patient information leaflets can increase fear and lower the intention to buy and the willingness to take a pain medication.

Abstract. Introduction:. Nocebo effects are defined as adverse events related to negative expectations and learning processes that are involved in the modulation of the descending pain pathways. Research over the last couple of decades has illustrated that behavioral, psychoneurobiological, and functional changes occur during nocebo-induced pain processing. Objectives:. We aimed to review published human and nonhuman research on algesia and hyperalgesia resulting from negative expectations and nocebo effects. Methods:. Herein, we searched and comprehensively reviewed scientific literature providing informative knowledge about the psychoneurobiological bases of the nocebo effect in the field of pain with an emphasis on how pain processes are shaped by both cognitive and noncognitive factors. Results:. Negative expectations are formed through verbal suggestions of heightened pain, prior nociceptive and painful experiences, and observation of pain in others. Susceptibility to the nocebo effect can be also influenced by genetic variants, conscious and nonconscious learning processes, personality traits, and psychological factors. Moreover, providers' behaviors, environmental cues and the appearance of medical devices can induce negative expectations that dramatically influence pain perception and processing in a variety of pain modalities and patient populations. Conclusion:. Importantly, we concluded that nocebo studies outline how individual expectations may lead to physiological changes underpinning the central integration and processing of magnified pain signaling. Further research is needed to develop strategies that can identify patients with nocebo-vulnerable pain to optimize the psychosocial and therapeutic context in which the clinical encounter occurs, with the ultimate purpose of improving clinical outcomes.

Abstract. Introduction:. Nocebo-induced algesic responses occurring within clinical contexts present a challenge for health care practitioners working in the field of pain medicine. Objectives:. Following the recent research on algesic nocebo effects, the scope of this review is to develop ethically acceptable strategies to help avoid, or at least reduce, nocebo responses within clinical settings. Methods:. We reviewed relevant clinical studies that depict how patient-practitioner interactions may contribute to the reduction of nocebo responses. Results:. A strong algesic nocebo effect may adversely impact a patient's condition by causing decreases in both the efficacy and effectiveness of interventions, as well as by promoting treatment nonadherence and discontinuation. These effects may be triggered through multiple channels and can lead to significant alterations in a patient's perception of pain, consequently producing a weakening of the specific positive effects of pharmacological, psychological, or physical pain-management interventions. Conclusion:. To minimize nocebo effects in clinical settings, we identified and discussed five contextual aspects relevant to the treatment of patients with chronic pain: (1) negative patient–clinician communication and interaction during treatment; (2) emotional burden of patients during treatment with analgesic medication; (3) negative information provided via informational leaflets; (4) cued and contextual conditioning nocebo effects; and (5) patient's lack of positive information. Through an understanding of these elements, many preventive and ethically acceptable clinical actions can be taken to improve multidisciplinary pain treatment outcomes.

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.

Objectives To examine qualitative responses regarding the use of placebo treatments in medical care in a sample of US patients.Survey studies suggest a deliberate clinical use of placebos by physicians, and prior research has found that although most US patients find placebo use acceptable, the rationale for these beliefs is largely unknown.Setting Members of the Outpatient Clinic at the Kaiser Permanente Northern California interviewed research participants who had been seen for a chronic health problem at least once in the prior 6 months.Participants 853 women (61%) and men, white (58%) and non-white participants aged 18–75 years.Primary and secondary outcomes Qualitative responses on perceptions of placebo use from one-time telephone surveys were analysed for common themes and associations with demographic variables.Results Prior results indicated that a majority of respondents felt it acceptable for doctors to recommend placebo treatments. Our study found that a lack of harm (n=291, 46.1%) and potential benefit (n=250, 39.6%) were the most common themes to justify acceptability of placebo use. Responses citing potential benefit were associated with higher education (r=0.787; p

Over the past two decades the placebo and nocebo effect has shifted from being a nuisance in clinical research to a promising model of an emerging neuroscience of mind-brain-body interactions. In fact, the interest in and the success of placebo research resides in its multifaceted meaning, which involves key issues in modern science - from neurobiology to philosophy, from ethics to social psychology, and from clinical trials design to medical practice. Thus, the placebo effect, which has long been neglected by the neuroscience community, is today considered a real and detectable biological phenomenon, and the question of whether placebos work has been reframed as to how they work. The aim of this review is to introduce the reader to the nature and extent of the placebo and nocebo phenomenon and to present the interesting implications of the new evidence that arises from recent research in the field of pain.