Association between expectations and clinical outcomes in online v. face-to-face therapy - an individual participant data meta-analysis.

BACKGROUND: Online treatments are increasing in number and are currently available for a wide range of clinical problems. To date little is known about the role of treatment expectations and other placebo-like mechanisms in online settings compared to traditional face-to-face treatment. To address this knowledge gap, we analyzed individual participant data from randomized clinical trials that compared online and face-to-face psychological interventions. METHODS: MEDLINE (Ovid) and PsycINFO (Ovid) were last searched on 2 February 2021. Randomized clinical trials of therapist guided online v. face-to-face psychological interventions for psychiatric or somatic conditions using a randomized controlled design were included. Titles, abstracts, and full texts of studies were independently screened by multiple observers. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was followed. Authors of the matching trials were contacted for individual participant data. Ratings from the Credibility and Expectancy Questionnaire and the primary outcome measure from each trial were used to estimate the association between expectation ratings and treatment outcomes in online v. face-to-face interventions, using a mixed-effects model. RESULTS: Of 7045 screened studies, 62 full-text articles were retrieved whereof six studies fulfilled the criteria and provided individual participant data (n = 491). Overall, CEQ ratings predicted clinical outcomes (ß = 0.27) at end of treatment with no moderating effect of treatment modality (online v. face-to-face). CONCLUSIONS: Online treatment appears to be equally susceptible to expectancy effects as face-to-face therapy. This furthers our understanding of the importance of placebo-like factors in online treatment and may aid the improvement of healthcare in online settings.

Efficacy of mecobalamin (vitamin B12) in the treatment of long-term pain in women diagnosed with fibromyalgia: protocol for a randomised, placebo-controlled trial.

INTRODUCTION: Fibromyalgia causes long-term pain. It affects at least 2% of the population, the majority being women. In addition, extended symptoms corresponding to vitamin B12 deficiency occur. Findings from several studies have indicated that vitamin B12 may be a possible treatment for pain in fibromyalgia. The aim of the proposed study is to evaluate whether vitamin B12 decreases pain sensitivity and the experience of pain (ie, hyperalgesia and allodynia) in women with fibromyalgia. METHODS AND ANALYSIS: The study is a randomised, placebo-controlled, single-blind, clinical trial with two parallel groups which are administered mecobalamin (vitamin B12) or placebo over 12 weeks. 40 Swedish women aged 20-70 years with an earlier recorded diagnosis of fibromyalgia are randomised into the placebo group or the treatment group, each consisting of 20 participants. Outcomes consist of questionnaires measured at baseline and after 12 weeks of treatment. A final re-evaluation will then follow 12 weeks after treatment ends. The primary outcome is tolerance time, maximised to 3 min, which is assessed using the cold pressor test. In order to broaden the understanding of the lived experience of participants, qualitative interviews will be conducted using a phenomenological approach on a lifeworld theoretical basis (reflective lifeworld research approach). ETHICS AND DISSEMINATION: The protocol for the study is approved by the local ethical committee at Linkoping (EPM; 2018/294-31, appendices 2019-00347 and 2020-04482). The principles of the Helsinki Declaration are followed regarding oral and written consent to participate, confidentiality and the possibility to withdraw participation from the study at any time. The results will primarily be communicated through peer-reviewed journals and conferences. TRIAL REGISTRATION NUMBER: NCT05008042.

Placebo Response and Media Attention in Randomized Clinical Trials Assessing Cannabis-Based Therapies for Pain: A Systematic Review and Meta-analysis.

Importance: Persistent pain is a common and disabling health problem that is often difficult to treat. There is an increasing interest in medicinal cannabis for treatment of persistent pain; however, the limited superiority of cannabinoids over placebo in clinical trials suggests that positive expectations may contribute to the improvements. Objective: To evaluate the size of placebo responses in randomized clinical trials in which cannabinoids were compared with placebo in the treatment of pain and to correlate these responses to objective estimates of media attention. Data Sources: A systematic literature search was conducted within the MEDLINE and Embase databases. Studies published until September 2021 were considered. Study Selection: Cannabinoid studies with a double-blind, placebo-controlled design with participants 18 years or older with clinical pain of any duration were included. Studies were excluded if they treated individuals with HIV/AIDS or severe skin disorders. Data Extraction and Synthesis: The study followed the Preferred Reporting Items for Systematic Review and Meta-analyses reporting guideline. Data were extracted by independent reviewers. Quality assessment was performed using the Risk of Bias 2 tool. Attention and dissemination metrics for each trial were extracted from Altmetric and Crossref. Data were pooled and analyzed using a random-effects statistical model. Main Outcomes and Measures: Change in pain intensity from before to after treatment, measured as bias-corrected standardized mean difference (Hedges g). Results: Twenty studies, including 1459 individuals (mean [SD] age, 51 [7] years; age range, 33-62 years; 815 female [56%]), were included. Pain intensity was associated with a significant reduction in response to placebo, with a moderate to large effect size (mean [SE] Hedges g, 0.64 [0.13]; P < .001). Trials with low risk of bias had greater placebo responses (q1 = 5.47; I2 = 87.08; P = .02). The amount of media attention and dissemination linked to each trial was proportionally high, with a strong positive bias, but was not associated with the clinical outcomes. Conclusions and Relevance: Placebo contributes significantly to pain reduction seen in cannabinoid clinical trials. The positive media attention and wide dissemination may uphold high expectations and shape placebo responses in future trials, which has the potential to affect the outcome of clinical trials, regulatory decisions, clinical practice, and ultimately patient access to cannabinoids for pain relief.

Development and cross-national investigation of a model explaining participation in WHO-recommended and placebo behaviours to prevent COVID-19 infection.

To protect themselves from COVID-19, people follow the recommendations of the authorities, but they also resort to placebos. To stop the virus, it is important to understand the factors underlying both types of preventive behaviour. This study examined whether our model (developed based on the Health Belief Model and the Transactional Model of Stress) can explain participation in WHO-recommended and placebo actions during the pandemic. Model was tested on a sample of 3346 participants from Italy, Japan, Poland, Korea, Sweden, and the US. It was broadly supported: objective risk and cues to action showed both direct and indirect (through perceived threat) associations with preventive behaviours. Moreover, locus of control, decision balance, health anxiety and preventive coping moderated these relationships. Numerous differences were also found between countries. We conclude that beliefs about control over health and perceived benefits of actions are critical to the development of interventions to improve adherence to recommendations.

Sharing clinical notes, and placebo and nocebo effects: Can documentation affect patient health?

This paper connects findings from the field of placebo studies with research into patients' interactions with their clinician's visit notes, housed in their electronic health records. We propose specific hypotheses about how features of clinicians' written notes might trigger mechanisms of placebo and nocebo effects to elicit positive or adverse health effects among patients. Bridging placebo studies with (a) survey data assaying patient and clinician experiences with portals and (b) randomized controlled trials provides preliminary support for our hypotheses. We conclude with actionable proposals for testing our understanding of the health effects of access to visit notes.

Does Certainty of Genuine Treatment Increase the Drug Response in Alzheimer's Disease Patients: A Meta-Analysis and Critical Discussion.

BACKGROUND: Non-specific treatment effects, such as expectations, contribute to the effectiveness of pharmacological treatments across diseases. However, the contribution of expectancy, i.e., certainty of receiving treatment, in patients with Alzheimer's disease (AD) is unknown. OBJECTIVE: The aim is to investigate whether certainty of receiving a genuine treatment influences the response to active treatment in AD patients. METHODS: The efficacy of active treatments in open-label trials, where patients are certain of receiving treatment (100%certainty), was compared to the same active treatments in randomized controlled trials (RCT), where patients are uncertain of receiving treatment or placebo (50%certainty). RESULTS: In the seven open-label trials, there was no significant difference between post- and pre-treatment scores (difference in means = 0.14, 95%CI [-0.51; 0.81], p = 0.66). In the eight RCT trials, there was a significant difference between post- and pre-treatment (difference in means = -0.91, 95%CI [-1.43; -0.41], p < 0.001). There was a statistically significant difference between open-label and RCT trials (difference = 1.06, 95%CI [0.23; 1.90], p = 0.001). CONCLUSION: Patients with AD did not benefit from certainty of receiving genuine treatment. This could be due to the nature/progression of the disease, but it could also be related to an order effect in the practice of running AD trials, where RCTs are conducted prior to open label. These findings have implications for the understanding of non-specific treatment effects in AD patients as well as for the design of clinical trials that test pharmacological treatments in AD.

Naltrexone during pain conditioning: A double-blind placebo-controlled experimental trial.

Naltrexone reversibly blocks the effects of opioids and has been shown to decrease placebo analgesia. However, it is not clear (1) to what extent naltrexone affects pain modulation in a nontreatment context, for example, in response to pain cues or (2) how naltrexone given prior to pain-cue learning shapes pain responses. In a double-blind procedure prior to pain-cue conditioning, 30 healthy participants were randomized to receive an oral dose of naltrexone (50 mg) or inert pill. During functional magnetic resonance imaging, high and low pain pressures were paired with two different visual cues: a high pain cue and a low pain cue (learning sequence). During a test sequence, medium levels of pressure were used for both cues and the difference in subjective pain ratings following high and low pain cues was calculated. Results showed significant conditioned pain responses across groups (P < .001); however, no significant difference between participants receiving naltrexone or inert pill (P = .193). There was a significant correlation between the difference in high and low pain ratings during the learning sequence and the effect of high and low pain cues during the test sequence (r = .575, P = .002). Functional magnetic resonance imaging analyses revealed no significant difference in brain activation between groups. Here, we demonstrate comparable learning of pain responses in participants treated with naltrexone or inert pill. The results point to the possibility that associative learning, and conditional responding to pain cues, is not dependent on endogenous opioids. Our results, using pain-cue conditioning to create reduced pain responses, contrast previous studies where opioid antagonists significantly reduced the placebo effect in treatment of pain.

Placebo Responses Among Men With Erectile Dysfunction Enrolled in Phosphodiesterase 5 Inhibitor Trials: A Systematic Review and Meta-analysis.

Importance: Placebo responses in the treatment of erectile dysfunction (ED) are poorly described in the literature to date. Objective: To quantify the association of placebo with ED outcomes among men enrolled in placebo-controlled, phosphodiesterase 5 inhibitor (PDE5I) trials. Data Sources: For this systematic review and meta-analysis, a database search was conducted to identify double-blind, placebo-controlled studies using PDE5Is for the treatment of ED published from January 1, 1998, to December 31, 2018, within MEDLINE, Embase, Cochrane Library, and Web of Science. Only articles published in the English language were included. Study Selection: Double-blind, placebo-controlled randomized clinical trials of PDE5Is for ED were included. Studies were excluded if they did not provide distribution measures for statistical analysis. Study selection review assessments were conducted by 2 independent investigators. A total of 2215 studies were identified from the database search, and after review, 63 studies that included 12 564 men were analyzed. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in abstracting data and assessing validity. Data were extracted from published reports by 2 independent reviewers. Quality assessment was performed using the Jadad scale. Data were pooled using a random-effects model. Main Outcomes and Measures: The main outcome was improvement in the erectile function domain of the International Index of Erectile Function questionnaire in the placebo arm of the included studies. Effect size was reported as bias-corrected standardized mean difference (Hedges g). The hypothesis was formulated before data extraction. Results: A total of 63 studies that included 12 564 men (mean [SD] age, 55 [7] years; age range, 36-68 years) were included. Erectile function was significantly improved among participants in the placebo arm, with a small to moderate effect size (Hedges g [SE], 0.35 [0.03]; P < .001). Placebo effect size was larger among participants with ED associated with posttraumatic stress disorder (Hedges g [SE], 0.78 [0.32]; P = .02) compared with the overall analysis. No significant difference was found between placebo and PDE5Is for ED after prostate surgery or radiotherapy (Hedges g [SE], 0.30 [0.17]; P = .08). Conclusions and Relevance: In this study, placebo was associated with improvement of ED, especially among men with ED-related posttraumatic stress disorder. No difference was found between placebo and PDE5I among men treated for ED after prostate surgery.

Shaping placebo analgesic responses on the Internet: a randomized experimental trial.

BACKGROUND: The field of Internet-based treatments is expanding. However, little is known about placebo effects in online therapeutic settings. The aim of this study was to test if placebo analgesia could be induced via online communication. Exploratory analyses tested if different communication styles (empathetic/neutral) would influence the placebo effect. METHODS: In this double-blind experiment, 30 healthy participants were randomized to either empathetic or neutral online communication. After completing the online modules, a face-to-face placebo analgesia experiment was performed. An independent experimenter (blinded as to communication type) performed the pain testing and treatment with a sham analgesic device (placebo). RESULTS: Overall, there was a significant placebo effect, as participants rated the pain lower when the sham analgesic device was turned on, compared to off. An additional control experiment (n = 17) confirmed that pain testing with the sham analgesic device per se, without any prior communication, was not enough to induce placebo effects. Exploratory analyses indicated a significant difference in perception of the online communication between participants randomized to the empathetic and neutral groups because the empathetic group rated the interaction as more positive. Also, there was a significant difference in online compliance. Yet, exploratory analyses did not suggest any difference in placebo pain ratings between the empathetic and neutral communication groups. CONCLUSION: The results in this study suggest that placebo effects can be created even when information about an analgesic treatment is delivered online. This is the first indication of a novel research line that investigates placebo effects in online treatment.

The pain alarm response - an example of how conscious awareness shapes pain perception.

Pain is subjective and largely shaped by context, yet, little is known about the boundaries for such influences, in particular in relation to conscious awareness. Here, we investigated processing of noxious stimuli during sleep. Four experiments were performed where participants (n = 114) were exposed to repetitions of noxious heat, either when awake or during sleep. A test-phase followed where participants were awake and exposed to painful stimuli and asked to rate pain. Two control experiments included only the test-phase, without any prior pain exposures. Participants in the awake condition rated all test-phase stimuli the same. Conversely, participants who had been sleeping, and thus unaware of getting noxious heat, displayed heightened pain during the first part of the test-phase. This heightened reaction to noxious stimuli-a pain alarm response-was further pronounced in the control conditions where participants were naïve to noxious heat. Results suggest that the pain alarm response is partly dependent on conscious awareness.

Certainty of genuine treatment increases drug responses among intellectually disabled patients.

OBJECTIVE: To determine the placebo component of treatment responses in patients with intellectual disability (ID). METHODS: A statistical meta-analysis comparing bias-corrected effect sizes (Hedges g) of drug responses in open-label vs placebo-controlled clinical trials was performed, as these trial types represent different certainty of receiving genuine treatment (100% vs 50%). Studies in fragile X, Down, Prader-Willi, and Williams syndrome published before June 2015 were considered. RESULTS: Seventeen open-label trials (n = 261, 65% male; mean age 23.6 years; mean trial duration 38 weeks) and 22 placebo-controlled trials (n = 721, 62% male; mean age 17.1 years; mean trial duration 35 weeks) were included. The overall effect size from pre to post treatment in open-label studies was g = 0.602 (p = 0.001). The effect of trial type was statistically significant (p = 0.001), and revealed higher effect sizes in studies with 100% likelihood of getting active drug, compared to both the drug and placebo arm of placebo-controlled trials. We thus provide evidence for genuine placebo effects, not explainable by natural history or regression toward the mean, among patients with ID. CONCLUSIONS: Our data suggest that clinical trials in patients with severe cognitive deficits are influenced by the certainty of receiving genuine medication, and open-label design should thus not be used to evaluate the effect of pharmacologic treatments in ID, as the results will be biased by an enhanced placebo component.