The Interplay Between Health Disparities and Acceptability of Virtual Reality: A Survey Study.

Virtual reality (VR) has emerged as a nonpharmacological adjuvant to manage acute and chronic pain symptoms. The goal of this survey study was to determine the acceptability of VR among chronic pain participants hailing from distressed and prosperous neighborhoods in the state of Maryland. We hypothesized that pain severity and interference vary in groups experiencing health disparities, potentially influencing VR's acceptability. From March 11 to March 15, 2020, we surveyed a cohort of clinically phenotyped participants suffering from chronic orofacial pain. Participants were asked to express their willingness to participate in a longitudinal VR study and their expectation of pain relief from using VR. Seventy out of 350 participants with chronic pain completed the survey (response rate: 20%). There was no difference in the likelihood of responding to the survey based on their neighborhood distress. Among survey respondents and nonrespondents, similar proportions of participants were from distressed neighborhoods. Among the respondents, 63 (90%) and 59 (84.3%) were willing to participate and expected to experience pain relief from the VR intervention, respectively. Age, sex, race, neighborhood distress, severity of pain, and prior VR experience did not influence willingness to participate in the VR trial or the expectations of VR-induced improvement. These findings suggest that VR as an adjuvant intervention is potentially accepted by chronic pain participants, irrespective of neighborhood-level social determinants of health.

Nocebo belief and attitudes towards side effect disclosure: A general population-based online survey in Europe and North America.

BACKGROUND: With evidence for large nocebo effects in pain, guidelines for nocebo-minimizing strategies regarding side effect disclosure are emerging. While the ethical implications and effectiveness of such strategies have been the subject of investigations, the perspective of healthcare users are missing despite the stakes for patient autonomy. METHODS: In an online survey, 2766 adults (≥18 years) from a general population sample in Europe and North America responded to questions related to nocebo familiarity, nocebo beliefs and attitudes towards side effect disclosure. RESULTS: Only 474 (17%) were familiar with nocebo terminology, while 1379 (50%) were familiar with the concept of nocebo side effects. Belief in nocebo side effects was not well-established; 738 (31%) agreed that side effect information could increase side effect occurrence. Nocebo belief was associated with more negative attitudes towards side effect disclosure and 1962 (73%) indicated that positive framing was an acceptable way of disclosing side effect information. In general, the majority of participants (65-76%) held positive attitudes towards the disclosure of all potential side effects and 2309 (84%) favoured patient autonomy over nonmaleficence. Although the general patterns were similar in the European and North American sample, the latter showed stronger nocebo belief and stronger positive attitudes towards side effect disclosure. CONCLUSIONS: The study found a consistent, moderate association between nocebo belief and attitudes towards nondisclosure, alongside positive attitudes towards the use of framing. Together with the discovered discrepancy between nocebo familiarity and nocebo belief, these findings have implications for the implementation of nocebo education and risk framing strategies. SIGNIFICANCE STATEMENT: This is the first large-scale, general population-based study to contribute to the scientific discussion about nocebo side effects from the perspective of healthcare users. The findings have implications for the discussion on how to handle the medical and ethical problem of nocebo side effects in clinical practice.

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

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

Transcriptomic Profiles Associated with Experimental Placebo Effects in Chronic Pain.

Gene expression networks associated with placebo effects are understudied; in this study, we identified transcriptomic profiles associated with placebo responsivity. Participants suffering from chronic pain underwent a verbal suggestion and conditioning paradigm with individually tailored thermal painful stimulations to elicit conditioned placebo effects. Participants reported pain intensity on a visual analog scale (VAS) anchored from zero = no pain to 100 = maximum imaginable pain. RNA was extracted from venous blood and RNA sequencing and validation tests were performed to identify differentially expressed genes (DEGs) associated with placebo effects, controlling for sex and level of pain. Unbiased enrichment analyses were performed to identify biological processes associated with placebo effects. Of the 10,700 protein-coding genes that passed quality control filters, 667 were found to be associated with placebo effects (FDR <0.05). Most genes (97%) upregulated were associated with larger placebo effects. The 17 top transcriptome-wide significant genes were further validated via RT-qPCR in an independent cohort of chronic pain participants. Six of them (CCDC85B, FBXL15, HAGH, PI3, SELENOM, and TNFRSF4) showed positive and significant (P < 0.05) correlation with placebo effects in the cohort. The overall DEGs were highly enriched in regulation of expression of SLITs and ROBOs (R-HSA-9010553, FDR = 1.26e-33), metabolism of RNA (R-HSA-8953854, FDR = 1.34e-30), Huntington's disease (hsa05016, FDR = 9.84e-31), and ribosome biogenesis (GO:0042254, FDR = 2.67e-15); alternations in these pathways might jeopardize the proneness to elicit placebo effects. Future studies are needed to replicate this finding and better understand the unique molecular dynamics of people who are more or less affected by pain and placebo.

Neuropsychological mechanisms of observational learning in human placebo effects.

Scientific evidence indicates that placebo effects are psychoneurobiological events involving the contribution of distinct central nervous systems and peripheral physiological mechanisms that influence pain perception and other symptoms. Placebo effects can occur without formal conditioning and direct prior experience because crucial information can be acquired through observational learning. Observation of benefits in another person results in placebo effects of a magnitude like those induced by directly experiencing an analgesic benefit. Understanding the psychological mechanisms of observationally induced placebo effects is a complex and multifaceted endeavor. While previous reviews have highlighted various frameworks and models to understand these phenomena, the underlying biological mechanisms have been overlooked. We summarize critically current understanding of its behavioral and neural mechanisms. Understanding the neural mechanisms of hypoalgesia driven by observation can serve as a foundation for future development of novel theoretical and methodological approaches and ultimately, applications.

Clinical Phenotypes Supporting the Relationship Between Sleep Disturbance and Impairment of Placebo Effects.

Lack of good sleep or insomnia can lead to many health issues, including an elevated risk of cardiovascular disease, obesity, fatigue, low mood, and pain. While chronic pain negatively impacts sleep quality, the relationship between descending pain modulatory systems like placebo effects and sleep quality is not thoroughly known. We addressed this aspect in a cross-sectional study in participants with chronic pain. Placebo effects were elicited in a laboratory setting using thermal heat stimulations delivered with visual cues using classical conditioning and verbal suggestions. We estimated the levels of insomnia severity with the Insomnia Severity Index and the sleep quality with the Pittsburg Sleep Quality Index. The previous night's sleep continuity was assessed as total sleep time, sleep efficiency, and sleep midpoint the night before the experiment. 277 people with chronic pain and 189 pain-free control individuals participated. Participants with chronic pain and insomnia showed smaller placebo effects than those with chronic pain without insomnia. Similarly, poor sleep quality was associated with reduced placebo effects among participants with chronic pain. Clinical anxiety measured by Depression Anxiety Stress Scales partially mediated these effects. In contrast, placebo effects were not influenced by the presence of insomnia or poor sleep quality in pain-free participants. Sleep continuity the night before the experiment did not influence the placebo effects. Our results indicate that participants who experience insomnia and/or poor sleep quality and chronic pain have smaller placebo effects, and that the previous night sleep continuity does not influence the magnitude of placebo effects. PERSPECTIVE: This study examined the relationship between sleep disturbances and experimentally induced placebo effects. We found that individuals with chronic pain who experience insomnia and poor sleep quality demonstrated reduced placebo effects compared to their counterparts with good sleep quality and no insomnia.

The desire for side-effect information in pain treatment: an experimental analysis of contextual and individual difference factors.

ABSTRACT: Informing patients about potential side effects of pain treatment is a requirement that protects patients and aids decision making, but it increases the likelihood of unwanted nocebo side effects. If patients do not desire all side-effect information, it may be possible to ethically reduce nocebo effects through authorized concealment of side effects, whereby patients and clinicians engage in shared decision-making to regulate the disclosure of side-effect information. Currently, there is no experimental data clarifying the factors that causally influence desire for side-effect information in pain treatment. In 2 cross-sectional, between-subjects scenario experiments (experiment 1 N = 498, experiment 2 N = 501), 18 to 79-year-old community adults learned about a lower back pain treatment, and potential side-effect severity, frequency, and duration were manipulated. Individual differences in information avoidance were also recorded. In both experiments, participants reported high desire for side-effect information, but the desire was reduced when side effects were described as less severe, less frequent, and participants scored high in information avoidance. Results were not moderated by participants' level of contact with the health care system, chronic health condition, or clinical pain history. Additional analyses indicated that low side-effect severity and frequency lessen desire for side-effect information because these variables reduce belief that side-effect information will be needed in the future and lower feelings of anticipated regret. The experiments identify situational and individual-difference factors that decrease the desire for side-effect information and provide evidence on when and for whom it may be useful for physicians to engage in shared medical decision-making with the goal of reducing nocebo side effects.

The Nocebo Effect.

Adverse nocebo responses can cause harm to patients and interfere with treatment adherence and effects in both clinic practice and clinical trials. Nocebo responses refer to negative outcomes to active medical treatments in clinical trials or practice that cannot be explained by the treatment's pharmacologic effects. Negative expectancies and nocebo effects are less known than placebo responses. Nocebo effects can be triggered by verbal suggestions, prior negative experiences, observation of others experiencing negative outcomes, and other contextual and environmental factors. As research advances over the years, mechanistic knowledge is accumulating on the neurobiological mechanisms of nocebo effects. This review summarizes studies on different facets of nocebo effects and responses and discusses clinical implications, ethical considerations, and future directions.

Pain experience in eating disorders: The mediating role of depression, alexithymia and interoceptive awareness.

OBJECTIVE: Evidence suggests reduced sensitivity to pain due to high pain threshold in anorexia and bulimia nervosa and a possible role of depression, alexithymia and interoceptive awareness on pain experience. This study examined whether self-report and real-time evoked pain experience were mediated by depression, alexithymia and interoceptive awareness in a comprehensive sample of patients with eating disorders (ED). METHOD: 145 participants (90 ED, 55 healthy controls (HC)) underwent a real-time evoked examination of pain and completed self-report questionnaires for pain (Pain Detect Questionnaire (PD-Q), PD-Q VAS, Leeds Assessment of Neuropathic Symptoms and Signs), depression (BDI-II), interoceptive awareness Multidimensional Assessment of Interoceptive Awareness (MAIA), and alexithymia (TAS-20). Three mediation models, with ED diagnosis as independent variable, and BDI, MAIA and TAS-20 as mediators, were tested. RESULTS: Participants with ED and HC exhibited similar pain type and intensity (self-report and real-time). Eating disorders diagnosis was associated with lower self-report pain intensity and non-neuropathic like pain experience (model 1-2). Depressive symptoms partially (model 1-2) or fully (model 3) mediated the association between ED diagnosis and pain experience, alone (model 1) or via alexithymia (model 3). Interoceptive awareness did not influence pain symptomatology. DISCUSSION: ED diagnosis is associated with non-neuropathic and lower pain experience. However, concurrent depression and alexithymia are associated with higher pain symptoms and neuropathic features. These results could inform clinicians about the influence of psychopathology on pain experience in ED.

Medical Extended Reality Trials: Building Robust Comparators, Controls, and Sham.

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.

Motivating older adults through immersive virtual exercise (MOTIVE): A randomized pilot study.

BACKGROUND: This study aimed to: 1) determine the feasibility of a virtual reality physical activity intervention among older adults and 2) test the preliminary effectiveness of the intervention at increasing physical activity and 3) decreasing depressive symptoms. METHODS: We included 10 older adults randomized into the Motivating Older Adults Through Immersive Virtual Exercise (MOTIVE) intervention group and 10 randomized into the physical activity education only control group. We analyzed the data using descriptive statistics and linear mixed models, testing the interaction of time and the treatment condition. RESULTS: Participants in the intervention group attended an average of 15 out of the 16 sessions. A total of 90% of MOTIVE intervention group participants "completely agreed" that the intervention was acceptable, (compared to 30% of education control group participants). CONCLUSION: This study supports testing the effectiveness of the intervention at improving physical activity and depressive symptoms in a larger sample of older adults.

Placebo effects in osteoarthritis: implications for treatment and drug development.

Osteoarthritis (OA) is the most common form of arthritis worldwide, affecting ~500 million people, yet there are no effective treatments to halt its progression. Without any structure-modifying agents, management of OA focuses on ameliorating pain and improving function. Treatment approaches typically have modest efficacy, and many patients have contraindications to recommended pharmacological treatments. Drug development for OA is hindered by the gradual and progressive nature of the disease and the targeting of established disease in clinical trials. Additionally, new medications for OA cannot receive regulatory approval without demonstrating improvements in both structure (pathological features of OA) and symptoms (reduced pain and/or improved function). In clinical trials, people with OA show high 'placebo responses', which hamper the ability to identify new effective treatments. Placebo responses refer to the individual variability in response to placebos given in the context of clinical trials and other settings. Placebo effects refer specifically to short-lasting improvements in symptoms that occur because of physiological changes. To mitigate the effects of the placebo phenomenon, we must first understand what it is, how it manifests, how to identify placebo responders in OA trials and how these insights can be used to improve clinical trials in OA. Leveraging placebo responses and effects in clinical practice might provide additional avenues to augment symptom management of OA.

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 Intricate Interaction Between Expectations and Therapeutic Outcomes of Psychedelic Agents.

This Viewpoint explores how expectations influence outcomes of psychedelic drug therapy.

Study protocol: randomised controlled trial of conditioned open-label placebo (COLP) for perioperative pain management in patients with head and neck cancer.

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.

Blinded Pain Cocktails: A Reliable and Safe Opioid Weaning Method.

Weaning opioids in patients with noncancerous chronic pain often poses a challenge when psychosocial factors complicate the patient's chronic pain syndrome and opioid use. A blinded pain cocktail protocol used to wean opioid therapy has been described since the 1970s. At the Stanford Comprehensive Interdisciplinary Pain Program, a blinded pain cocktail remains a reliably effective medication-behavioral intervention. This review (1) outlines psychosocial factors that may complicate opioid weaning, (2) describes clinical goals and how to use blinded pain cocktails in opioid tapering, and (3) summarizes the mechanism of dose-extending placebos and ethical justification of its use in clinical practice.

Effectiveness of Conditioned Open-label Placebo With Methadone in Treatment of Opioid Use Disorder: A Randomized Clinical Trial.

Importance: Methadone treatment is the most effective evidence-based treatment for opioid use disorder (OUD), but challenges related to dosing and premature treatment dropout argue for adjunct interventions to improve outcomes. One potential behavioral intervention with low risk involves harnessing placebo effects. Objective: To determine the effect of a pharmacologically conditioned open-label placebo (C-OLP) on 90-day methadone dose, retention, drug use, withdrawal, craving, quality of life, and sleep. Design, Setting, and Participants: This 2-arm, open-label, single-blind randomized clinical trial was conducted between December 5, 2017, and August 2, 2019, in an academically affiliated community opioid treatment program. Analyses were conducted between October 1, 2019, and April 30, 2020. A total of 320 newly enrolled adults seeking treatment for moderate to severe OUD were assessed for study eligibility; 131 met eligibility criteria, provided informed consent, and were randomized to either C-OLP or treatment as usual (TAU) in an unequal-block (3:2) manner. Exclusion criteria were pregnancy, hospital/program transfers, and court-ordered treatment. Interventions: Participants randomized to C-OLP received pharmacologic conditioning and a placebo pill and methadone, and participants randomized to TAU were given methadone only. Participants met with the study team 5 times: at baseline (treatment intake) and 2, 4, 8, and 12 weeks postbaseline. Interactions were balanced between the 2 groups. Main Outcomes and Measures: Outcomes included 90-day methadone dose (primary) and treatment retention, drug use, withdrawal, craving, quality of life, and sleep quality (secondary). Analyses were conducted as intention-to-treat. Results: Of the 131 people enrolled in the study, 54 were randomized to TAU and 77 to C-OLP. Mean (SD) age was 45.9 (11.2) years; most of the participants were Black or African American (83 [63.4%]) and male (84 [64.1%]). No significant group differences were observed in the mean (SD) 90-day methadone dose (83.1 [25.1] mg for group TAU, 79.4 [19.6] mg for group C-OLP; t = 0.621991; P = .43), but the groups differed significantly in their retention rates: 33 (61.1%) for TAU and 60 (77.9%) for C-OLP (χ21 = 4.356; P = .04; number needed to treat for the beneficial outcome of 3-month treatment retention, 6; 95% CI, 4-119). C-OLP participants also reported significantly better sleep quality. Conclusions and Relevance: In this randomized clinical trial, C-OLP had no effect on the primary outcome of 90-day methadone dose. However, C-OLP participants were significantly more likely to remain in treatment. These findings support the use of C-OLP as a methadone treatment adjunct, but larger trials are needed to further examine the use of C-OLP. Trial Registration: ClinicalTrials.gov Identifier: NCT02941809.

Adjunctive virtual reality pain relief after traumatic injury: a proof-of-concept within-person randomized trial.

ABSTRACT: In this study, we hypothesized that immersive virtual reality (VR) environments may reduce pain in patients with acute traumatic injuries, including traumatic brain injuries. We performed a randomized within-subject study in patients hospitalized with acute traumatic injuries, including traumatic brain injury with moderate pain (numeric pain score ≥3 of 10). We compared 3 conditions: (1) an immersive VR environment (VR Blu), (2) a content control with the identical environment delivered through nonimmersive tablet computer (Tablet Blu), and (3) a second control composed of donning VR headgear without content to control for placebo effects and sensory deprivation (VR Blank). We enrolled 60 patients, and 48 patients completed all 3 conditions. Objective and subjective data were analyzed using linear mixed-effects models. Controlling for demographics, baseline pain, and injury severity, we found differences by conditions in relieving pain (F 2,75.43 = 3.32, P = 0.042). VR Blu pain reduction was greater than Tablet Blu (-0.92 vs -0.16, P = 0.043), but VR Blu pain reduction was similar to VR Blank (-0.92 vs -1.24, P = 0.241). VR Blu was perceived as most effective by patients for pain reduction (F 2,66.84 = 16.28, P < 0.001), and changes in measures of parasympathetic activity including heart rate variability (F 2,55.511 = 7.87, P < 0.001) and pupillary maximum constriction velocity (F 2,61.41 = 3.50, 1-tailed P = 0.038) echoed these effects. There were no effects on opioid usage. These findings outlined a potential clinical benefit for mollifying pain related to traumatic injuries.

Individual Dimensions of Pain Catastrophizing Do Not Mediate the Effect of Sociodemographic and Psychological Factors on Chronic Orofacial Pain Severity, Interference, and Jaw Limitation: A Structural Equation Modeling Approach.

Pain catastrophization (PC), involving rumination, magnification, and helplessness, can be viewed as a coping strategy associated with chronic pain. PC is considered a driving force in mediating pain-related outcomes, but it is still unclear whether PC mediates the relationship between psychological and sociodemographic factors with chronic pain when considered in a single model. Using baseline data from a parent study, this study examined the effect of positive and negative psychological and sociodemographic factors on pain severity, interference, and jaw limitation mediated by the PC dimensions in a sample of 397 temporomandibular disorder (TMD) participants using structural equation modeling (SEM). SEM revealed that pain severity regressed on age, sex, education, and income; interference regressed on positive and negative psychological factors, education, and income; and jaw limitation regressed on age. The PC dimensions did not individually mediate these relationships. Although they jointly mediated the relationships between negative psychological factors and pain severity and between age and pain interference, the effect size was small, suggesting that PC is not a critical factor in mediating TMD pain outcomes. Reducing negative cognitions, not just PC, may be of greatest benefit to the most vulnerable TMD populations. PERSPECTIVE: This study examines sociodemographic and psychological factors that affect orofacial pain, finding that the pain catastrophizing dimensions do not mediate these relationships. Understanding which factors most strongly affect pain outcomes will help identify targets for intervention to produce the greatest benefit for the most vulnerable persons suffering from pain.