Placebo Hypoalgesia and Nocebo Hyperalgesia Induced by Observational Learning May Be Difficult to Disentangle in a Laboratory Setting.

Observational learning (OBL) (seeing pain/pain treatment in others) can evoke placebo hypoalgesia and nocebo hyperalgesia. Data that compare these effects and illuminates the role of expectations and empathy are scarce. Healthy participants (n = 105) were randomized to: 1) placebo OBL, 2) nocebo OBL, or 3) no-observation control group. OBL consisted of a model simulating pain relief or increase after a sham ointment was applied to one arm. Pain was evoked with thermal stimuli on both arms (ointment, contralateral) at baseline and postobservation. Expectations, pain ratings, and physiological data (eg, skin conductance level) were collected. A 3 × 2 × 2 (Group × Arm × Phase) mixed analyses of variance revealed a 3-way interaction that confirmed that OBL modulates pain: F(2, 93) = 6.08, P = .003, ηp2 = .12. Significant baseline-to-post-observation pain increases were shown in the nocebo OBL group, with a bigger increase for the arm with ointment (both P ≤ .007). In the placebo OBL group, pain was higher for the contralateral relative to the ointment arm (P < .001). Baseline-to-post-observation pain increase was significant for the contralateral arm (P < .001). Expectation mediated these effects. Skin conductance level decreased over time during ointment trials in the nocebo OBL group, suggesting reduced physiological arousal. The findings illustrate that OBL modulates pain through expectations. In the placebo OBL group, the pain did not decrease for the ointment but increased for the contralateral stimuli, which may reflect nocebo learning. Experimental OBL paradigms typically examine relative differences between ointment and contralateral cues. This can complicate disentangling placebo hypoalgesia and nocebo hyperalgesia in laboratory settings. Implications for existing theories are discussed. PERSPECTIVE: Data that systematically compare placebo hypoalgesia and nocebo hyperalgesia induced by OBL are scarce. The current work illustrates that these effects may be more difficult to disentangle than previously assumed, which could have implications for existing theories on OBL and placebo effects and their translation to clinical practice.

Learning pain from others: a systematic review and meta-analysis of studies on placebo hypoalgesia and nocebo hyperalgesia induced by observational learning.

ABSTRACT: Observing someone experience pain relief or exacerbation after an intervention may induce placebo hypoalgesia or nocebo hyperalgesia. Understanding the factors that contribute to these effects could help in the development of strategies for optimizing treatment of chronic pain conditions. We systematically reviewed and meta-analyzed the literature on placebo hypoalgesia and nocebo hyperalgesia induced by observational learning (OL). A systematic literature search was conducted in the databases PubMed, PsycINFO, Web of Science, ScienceDirect, PsycARTICLES, Scopus, and Academic Search Ultimate. Twenty-one studies were included in the systematic review, 17 of which were suitable for meta-analysis (18 experiments; n = 764 healthy individuals). The primary end point was the standardized mean difference (SMD) for pain following placebo cues associated during OL with low vs high pain. Observational learning had a small-to-medium effect on pain ratings (SMD 0.44; 95% confidence interval [CI] 0.21-0.68; P < 0.01) and a large effect on pain expectancy (SMD 1.11; 95% CI 0.49-2.04; P < 0.01). The type of observation (in-person vs videotaped) modulated the magnitude of placebo hypoalgesia/nocebo hyperalgesia ( P < 0.01), whereas placebo type did not ( P = 0.23). Finally, OL was more effective when observers' empathic concern (but no other empathy-related factors) was higher ( r = 0.14; 95% CI 0.01-0.27; P = 0.03). Overall, the meta-analysis demonstrates that OL can shape placebo hypoalgesia and nocebo hyperalgesia. More research is needed to identify predictors of these effects and to study them in clinical populations. In the future, OL could be an important tool to help maximize placebo hypoalgesia in clinical settings.

Can contagious itch be affected by positive and negative suggestions?

Contagious itch can be evoked by observing people scratching. Verbal suggestions about to-be-received itch can influence itch intensity, as shown by placebo research, but it is unknown whether this extends to contagious itch. The current study aimed to replicate prior findings that listening to scratching and rubbing sounds elicits contagious itch, and to investigate whether suggestions can modulate this process. Healthy participants (n = 140) received positive or negative suggestions about itch in response to the sounds (aimed to decrease or increase expected itch, respectively), or no specific suggestions as a control. Participants listened to a number of audio fragments with scratching and rubbing sounds. The amount of expected itch as well as itch sensation after each audio fragment were measured by self-report. Suggestions had no effect on the expected itch. Both rubbing and scratching sounds significantly elicited itch in all groups. Scratching sounds induced more itch than rubbing sounds exclusively in the control group. These findings indicate that short suggestions might be not effective enough to modify the expectations of people regarding contagious itch. Furthermore, suggestions modulate contagious itch to some degree, but not in the hypothesized direction. Potential similarities and differences in the neurobiological mechanisms of contagious itch and nocebo effects are discussed.

Associations Between Interindividual Differences, Expectations and Placebo and Nocebo Effects in Itch.

Introduction: Placebo and nocebo effects are positive and negative health outcomes that can be elicited by the psychosocial context. They can be mediated by expectations, and may emerge in somatic symptoms even when people are aware of these effects. Interindividual differences (e.g., in personality, affective states) could impact placebo and nocebo responding, but findings are inconsistent. Methods: The current work examined expectation as a mediator of the association between verbal placebo and nocebo suggestions (VSs) and histamine-induced itch across three experimental studies. Moreover, we examined whether interindividual differences (e.g., in optimism, neuroticism, behavioral activation system (BAS), body ignorance) modulated: (1) the direct association between VSs and itch (direct moderation), and (2) the indirect, expectation-mediated association between VSs and itch (moderated mediation). Positive VSs were compared to neutral instructions (Study 1; n = 92) or negative VSs (Studies 2+3; n = 203) in an open-label (i.e., explaining placebo and nocebo effects) or closed-label (concealed) context using PROCESS. First, mediation of VSs effects on itch by expectations was tested. Next, moderation by individual traits was explored using conditional process analyses. Results: The effects of VSs on itch were significantly mediated by expectation in Study 1 and in the open-label (but not closed-label) contexts of Studies 2 and 3. Ignorance of bodily signals marginally moderated the direct effects of VSs on itch when closed-label suggestions were given: at low levels of body ignorance, effects of positive and negative VSs were stronger. Moreover, moderated mediation was observed in the open-label groups of Studies 2 and 3: The expectation-mediated effects of VSs on itch were stronger when BAS drive was lower. Conclusion: Overall, the effects of VSs on itch were mediated by expectations in the open-label, but not the closed-label context. Moreover, the current work suggests that placebo and nocebo effects may be moderated by ignorance of bodily signals and the BAS. There was limited evidence that other interindividual differences modulated placebo and nocebo responding in itch.

What Should Clinicians Tell Patients about Placebo and Nocebo Effects? Practical Considerations Based on Expert Consensus.

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

Open- and Closed-Label Placebo and Nocebo Suggestions About a Sham Transdermal Patch.

OBJECTIVE: Placebo effects may occur when it is known that an inert substance is given (i.e., open-label placebo). It is not yet clear whether these effects are similar to concealed (i.e., closed-label) placebo effects for itch or whether nocebo effects can be induced under open-label conditions. METHODS: Healthy volunteers (n = 112) were randomized to an open-label (I) or closed-label (II) positive suggestions group, or an open-label (III) or closed-label (IV) negative suggestions group. Participants were told, as cover story, that a transdermal caffeine patch would be applied that positively influences cognitive abilities and, as a side effect, positively or negatively (depending on group allocation) influences itch. Participants in the open-label groups were given a rationale explaining placebo and nocebo effect mechanisms. Itch (the primary outcome) was induced at baseline and postsuggestions by histamine iontophoresis. RESULTS: Analyses of variance revealed significantly lower itch in the positive compared with the negative suggestions groups for both open- and closed-label contexts (all, p ≤ .008, Cohen d ≥ 0.47). Self-rated skin response was less severe after positive versus negative suggestions (all, p ≤ .017, Cohen d ≥ 0.33), but no effects on physical skin response were found (all, p ≥ .23, Cohen d ≤ 0.30). CONCLUSIONS: Itch can be reduced by positive compared with negative suggestions under both open- and closed-label conditions. These findings indicate that open-label suggestions may potentially be a tool to use placebo effects for self-reported outcomes in clinical practice, for example, by explaining the role of expectancy in treatment. It needs to be investigated further under which circumstances an open-label rationale may impact placebo and nocebo effects.Trial Registration:www.trialregister.nl; NTR7174.

Placebo and nocebo effects for itch and itch-related immune outcomes: A systematic review of animal and human studies.

Placebo and nocebo effects can influence somatic symptoms such as pain. For itch and other dermatological symptoms these effects have been far less investigated. This review systematically integrates evidence from both animal (mainly rodents) and human trials on placebo and nocebo effects in itch, itch-related symptoms and conditions of the skin and mucous membranes, and related immune outcomes (e.g., histamine). Thirty-one animal studies, and fifty-five human studies (k = 21 healthy participants, k = 34 patients) were included. Overall, studies consistently show that placebo and nocebo effects can be induced by various methods (e.g., suggestions, conditioning and social cues), despite high heterogeneity across studies. Effects of suggestions were found consistently across subjective and behavioral parameters (e.g., itch and scratching in humans), whereas conditioning was likely to impact physiological parameters under certain conditions (e.g., conditioning of histamine levels in stressed rodents). Brain areas responsible for itch processing were associated with nocebo effects. Future research may investigate how variations in methods impact placebo and nocebo effects, and whether all symptoms and conditions can be influenced equally.

Antipruritic Placebo Effects by Conditioning H1-antihistamine.

OBJECTIVE: Allergic rhinitis symptoms can be reduced by behaviorally conditioning antihistamine. It is unclear whether these findings extend to histamine-induced itch or work when participants are informed about the conditioning procedure (open-label conditioning). The current study aims to investigate the efficacy of (open-label) antipruritic behavioral conditioning for histamine-induced itch. METHODS: Healthy participants (n = 92; 84% female) were randomized to I) an open-label conditioned, II) closed-label conditioned, III) conditioned-not-evoked control, or IV) nonconditioned control group. A two-phase conditioning paradigm was used. During acquisition, a conditioned stimulus (CS; distinctively tasting beverage) was repeatedly paired with the H1-antihistamine levocetirizine (groups I-III). During evocation, the CS was paired with placebo (I, II), or instead of the CS, water was paired with placebo (III). The nonconditioned control group (IV) received CS with placebo in both phases. Itch after histamine iontophoresis and physiological data (i.e., spirometry, heart rate, skin conductance) were assessed. Combined conditioned and combined control groups were first compared, and analyses were repeated for separate groups. RESULTS: Marginally lower itch was reported in the combined conditioned compared with the control groups (F(1,88) = 2.10, p = .076, ηpartial = 0.02); no differences between separate groups were found. No effects on physiological data were found, except for heart rate, which reduced significantly and consistently for control groups, and less consistently for conditioned groups (group by time interaction: F(7,80) = 2.35, p = .031, ηpartial = 0.17). CONCLUSION: Limited support was found for the efficacy of antipruritic behavioral conditioning, regardless of whether participants were informed about the conditioning procedure. The application of open-label conditioning in patient populations should be further researched. TRIAL REGISTRATION: www.trialregister.nl; ID NTR5544.

Can verbal suggestions strengthen the effects of a relaxation intervention?

Short stress management interventions such as relaxation therapy have demonstrated preliminary effectiveness in reducing stress-related problems. A promising tool to strengthen the effectiveness of relaxation-based interventions is the use of verbal suggestions, as previous research provided evidence that verbal suggestions can induce positive outcome expectancies, facilitate adaptive responses to stress and improve health outcomes. The present experimental proof-of-concept study aimed to investigate the effects of a brief relaxation intervention and specifically the role of verbal suggestions on stress-related outcomes assessed by self-report questionnaires and psychophysiological data. 120 participants (mean age = 22.1 years) were randomized to one of four intervention conditions: a brief relaxation intervention plus verbal suggestions condition, a brief relaxation intervention only condition, a verbal suggestions only condition, and a control condition. Afterwards, participants were subjected to a psychosocial stress challenge to assess reactivity to a stressful event. Immediately after both relaxation interventions (with and without verbal suggestions), lower self-reported state anxiety was found compared to the control condition, but no differences were observed in response to the stressor. The verbal suggestions only condition did not impact state anxiety. No significant effects were found for verbal suggestion interventions on cortisol, alpha amylase, heart rate and skin conductance. This is the first study investigating the role of verbal suggestions in the effectiveness of a brief relaxation intervention. Although this experimental proof-of-concept study provides support for the effectiveness of a brief relaxation intervention in lowering state anxiety directly after the intervention, the effects did not impact the response to a subsequent stressor and we did not observe any evidence for the add-on effectiveness of verbal suggestions. The effectiveness of brief relaxation interventions on stress responses should be investigated further in future research by incorporating interventions that are tailored to the specific stress challenge and various types of verbal suggestions.

Effects of Open- and Closed-Label Nocebo and Placebo Suggestions on Itch and Itch Expectations.

Placebo and nocebo effects have been shown to influence subjective symptoms such as itch. These effects can be induced by influencing outcome expectations through, for example, combining the application of an inert substance (e.g., a cream) with verbal suggestions on the anticipated effects of this substance. Interestingly, placebo effects also occur when it is known that a treatment is inert (i.e., open-label placebo). However, no study to date has examined the efficacy of negative and positive verbal suggestions under similar open-label and closed-label (i.e., concealed placebo/nocebo) conditions in itch. A randomized controlled between-subjects study design was applied in which healthy volunteers (n = 92) were randomized to 1) an open-label positive verbal suggestion group, 2) a closed-label positive verbal suggestion group, 3) an open-label negative verbal suggestion group, or 4) a closed-label negative verbal suggestion group. Verbal suggestions were made regarding the topical application of an inert substance. Itch was evoked experimentally by histamine iontophoresis at baseline and again following suggestions. Itch expectations, self-reported itch during and following iontophoresis, and skin response parameters were measured. Positive suggestions were found to result in significantly lower expected itch than were negative suggestions in both open- and closed-label conditions. No effects of the suggestions on itch during iontophoresis were found, but significantly lower itch was reported in the 4 min following iontophoresis in the (combined open- and closed-label) positive compared with negative verbal suggestion groups. In addition, a smaller increase in skin temperature was found in the positive compared with negative suggestion groups. The findings illustrate a potential role of (open- and closed-label) placebo for optimizing expectations and treatment effects for itch in clinical practice. Clinical Trial Registration: Netherlands Trial Register, trial number: NTR6530.

Placebo Effects of Open-label Verbal Suggestions on Itch.

Placebo effects are positive outcomes that are not due to active treatment components, which may be elicited even when patients are aware of receiving an inert substance (open-label). This proof-of-principle study investigated for the first time whether open-label placebo effects on itch can be induced by verbal suggestions alone. Ninety-two healthy volunteers were randomized to experimental (open-label suggestions) or control (no suggestions) groups. Self-reported itch evoked by histamine iontophoresis was the primary study outcome. In addition, itch expectations, skin condition and affect were assessed. The experimental group expected lower itch than the control group, which was, in turn, related to less experienced itch in this group only, although no significantly different itch levels were reported between groups. The results illustrate a potential role for open-label placebo effects in itch, and suggest that further study of verbal suggestions through an extensive explanation of placebo effects might be promising for clinical practice.

Conditioning Immune and Endocrine Parameters in Humans: A Systematic Review.

BACKGROUND: Conditioned pharmacological effects may provide relevant clinical opportunities to improve treatment for patients with a variety of conditions. The aim of this systematic review was to create an overview of studies in this field of research and to investigate whether specific characteristics of the study design make for successful conditioning. METHODS: The protocol of this review was registered in Prospero (PROSPERO 2015: CRD42015024148). A systematic literature search was conducted in the databases PubMed, Embase, and PsychInfo. Studies were included if they were placebo-controlled trials in humans in which the effects of a pharmacological agent on immune or endocrine outcomes (e.g., interleukin-2 and cortisol) were conditioned, using a specific conditioned stimulus. The risk of bias of each study was assessed using the Cochrane risk-of-bias tool. RESULTS: The final selection included 16 studies. Overall, those studies indicate that conditioning of immunosuppression, conditioning of allergic responses, and conditioning of insulin and glycemic responses is possible. Regarding immunostimulants, antiallergic effects, and cortisol conditioning, the preliminary results are promising, but additional studies are needed. CONCLUSIONS: This systematic review shows classical conditioning of immune and endocrine responses for various pharmaceutical substances. The studies reviewed here indicate that the number of acquisition and evocation sessions, and characteristics of the unconditioned and conditioned stimuli, are important determinants of the effectiveness of pharmacological conditioning on immune and endocrine parameters. In the future, conditioned pharmacological effects may be used clinically as adjunct therapy in various patient populations.

C-reactive protein and fibrinogen in non-obstructive coronary artery disease as related to depressive symptoms and anxiety: findings from the TweeSteden Mild Stenosis Study (TWIST).

OBJECTIVE: The majority of acute coronary syndromes occur in the absence of obstructive coronary artery disease (CAD), and the underlying biobehavioral processes are not well understood. Depressive symptoms and anxiety are predictive of prognosis, and have been associated with markers of inflammation that play a role in atherosclerosis. This study examines whether depressive symptoms and anxiety are associated with higher levels of high-sensitive C-reactive protein (hs-CRP) and fibrinogen in patients with non-obstructive CAD. METHODS: Patients with non-obstructive CAD ("wall irregularities", stenosis<60%, N=414, mean age 62.1 ± 9.3 years, 52% women) in the TweeSteden Mild Stenosis (TWIST) observational cohort study completed the Hospital Anxiety and Depression Scale (HADS). Blood samples were analyzed for hs-CRP and fibrinogen. The cross-sectional association of anxiety and depressive symptoms with hs-CRP and fibrinogen, adjusting for covariates, was examined by multivariate regression analysis. RESULTS: Depressive symptoms were positively associated with hs-CRP level (ß=.135, p=.009), but not fibrinogen (ß=.075, p=.153), adjusted for age and sex. Additional adjustments for sociodemographic, disease severity and lifestyle factors rendered the association non-significant. In the fully adjusted model, depressive symptoms were not associated with hs-CRP (ß=.036, p>0.10) and BMI was the only variable that was independently associated with hs-CRP (ß=.203, p<.001). No associations were observed for anxiety with either hs-CRP or fibrinogen (p>0.10). CONCLUSION: Among patients with non-obstructive CAD, depressive symptoms and anxiety were not independently associated with hs-CRP and fibrinogen.