Ben Colagiuri

Participant expectancies in double-blind randomized placebo-controlled trials: potential limitations to trial validity

Background Randomized controlled trials (RCTs) that use placebo controls to achieve double-blinding intend to establish the efficacy of a treatment over and above expectancy and other forms of bias. Despite this, a growing body of research suggests that participant expectancies can influence the outcomes of these trials. Purpose and Methods This nonsystematic review examines research assessing the role of participant expectancies in double-blind placebo-controlled RCTs in order to determine if and how they can limit these types of trials. Results There appear to be at least three ways in which participant expectancies can limit the validity of double-blind placebo-controlled RCTs. First, when blinding fails researches cannot determine whether any observed improvement in the group receiving active treatment resulted because of the treatment’s effect or because of participants’ expectancies. Second, participant expectancies could create ceiling effects if there are strong placebo effects in each treatment arm and this may falsely suggest that the active treatment is ineffective without expectancy. Third, the knowledge that a participant will be allocated active treatment or placebo in double-blind placebo-controlled RCTs is likely to lead to weaker treatment responses than would be expected in standard clinical practice, in which patients are unlikely to doubt that they have been given an active treatment. Conclusions Participants’ expectancies can undermine the validity of double-blind placebo-controlled RCTs. Researchers conducting these trials should assess participants’ beliefs about their treatment allocation and actively investigate if and how these beliefs may have influenced the trial’s outcome. Clinical Trials 2010; 7: 246—255. http://ctj.sagepub.com

The placebo effect: From concepts to genes

Despite its initial treatment as a nuisance variable, the placebo effect is now recognized as a powerful determinant of health across many different diseases and encounters. This is in light of some remarkable findings ranging from demonstrations that the placebo effect significantly modulates the response to active treatments in conditions such as pain, anxiety, Parkinsons disease, and some surgical procedures. Here, we review pioneering studies and recent advances in behavioral, neurobiological, and genetic influences on the placebo effect. Consistent with recent conceptualizations, the placebo effect is presented as the product of a general expectancy learning mechanism in which verbal, conditioned, and social cues are centrally integrated to change behaviors and outcomes. Examples of the integration of verbal and conditioned cues, such as instructed reversal of placebo effects are also incorporated into this model. We discuss neuroimaging studies that have identified key brain regions and modulatory mechanisms underlying placebo effects using well-established behavioral paradigms. Finally, we present a synthesis of recent genetics studies on the placebo effect, highlighting a promising link between genetic variants in the dopamine, opioid, serotonin, and endocannabinoid pathways and placebo responsiveness. Greater understanding of the behavioral, neurobiological, and genetic influences on the placebo effect is critical for evaluating medical interventions and may allow health professionals to tailor and personalize interventions in order to maximize treatment outcomes in clinical settings.

A Systematic Review of the Effect of Expectancy on Treatment Responses to Acupuncture

Randomised controlled trials (RCTs) of acupuncture often find equivalent responses to real and placebo acupuncture despite both appearing superior to no treatment. This raises questions regarding the mechanisms of acupuncture, especially the contribution of patient expectancies. We systematically reviewed previous research assessing the relationship between expectancy and treatment responses following acupuncture, whether real or placebo. To be included, studies needed to assess and/or manipulate expectancies about acupuncture and relate these to at least one health-relevant outcome. Nine such independent studies were identified through systematic searches of Medline, PsycInfo, PubMed, and Cochrane Clinical Trials Register. The methodology and reporting of these studies were quite heterogeneous, meaning that meta-analysis was not possible. A descriptive review revealed that five studies found statistically significant effects of expectancy on a least one outcome, with three also finding evidence suggestive of an interaction between expectancy and type of acupuncture (real or placebo). While there were some trends in significant effects in terms of study characteristics, their generality is limited by the heterogeneity of study designs. The differences in design across studies highlight some important methodological considerations for future research in this area, particularly regarding whether to assess or manipulate expectancies and how best to assess expectancies.

Fifteen Minutes of Chair-Based Yoga Postures or Guided Meditation Performed in the Office Can Elicit a Relaxation Response

This study compared acute (15 min) yoga posture and guided meditation practice, performed seated in a typical office workspace, on physiological and psychological markers of stress. Twenty participants (39.6 ± 9.5 yr) completed three conditions: yoga, meditation, and control (i.e., usual work) separated by ≥24 hrs. Yoga and meditation significantly reduced perceived stress versus control, and this effect was maintained postintervention. Yoga increased heart rate while meditation reduced heart rate versus control (P < 0.05). Respiration rate was reduced during yoga and meditation versus control (P < 0.05). Domains of heart rate variability (e.g., SDNN and Total Power) were significantly reduced during control versus yoga and meditation. Systolic and diastolic blood pressure were reduced secondary to meditation versus control only (P < 0.05). Physiological adaptations generally regressed toward baseline postintervention. In conclusion, yoga postures or meditation performed in the office can acutely improve several physiological and psychological markers of stress. These effects may be at least partially mediated by reduced respiration rate.

Prevalence and Predictors of Sleep Difficulty in a National Cohort of Women with Primary Breast Cancer Three to Four Months Postsurgery

CONTEXT Mounting evidence suggests that many cancer patients suffer from sleep difficulty, but there is conflicting evidence regarding the prevalence and predictors of this adverse symptom. OBJECTIVES The present study investigated the prevalence and predictors of clinically significant sleep difficulty in women with primary breast cancer. METHODS Danish women (n=3343) with primary breast cancer completed the Pittsburgh Sleep Quality Index (PSQI) along with measures of depression, anxiety, physical activity/functioning, and health behaviors three to four months postsurgery. Data on disease status, treatment, and comorbidity were obtained from the Danish Cancer Cooperative Group and surgical departments, and information on sociodemographic factors and psychiatric history was obtained from Danish national longitudinal registries. RESULTS More than half (57.9%) of the women reported clinically significant sleep difficulty (PSQI >5). Multiple logistic regression identified seven significant predictors of sleep difficulty in the full sample. In order of strength, these were the following: more depressive symptoms, poorer physical functioning, older age, higher levels of trait anxiety, consuming more cigarettes, having undergone lumpectomy, and lower levels of physical activity. Subgroup analysis found that more depressive symptoms and poorer physical functioning were the only two predictors that were significant in both pre- and postmenopausal women. CONCLUSION These findings indicate that a high proportion of women with breast cancer experience sleep difficulty. Depression and poorer physical functioning appear to be robust predictors of sleep difficulty, whereas other predictors may depend on sample characteristics, including menopausal status.

Effect of an office worksite-based yoga program on heart rate variability: outcomes of a randomized controlled trial

BackgroundChronic work-related stress is an independent risk factor for cardiometabolic diseases and associated mortality, particularly when compounded by a sedentary work environment. The purpose of this study was to determine if an office worksite-based hatha yoga program could improve physiological stress, evaluated via heart rate variability (HRV), and associated health-related outcomes in a cohort of office workers.MethodsThirty-seven adults employed in university-based office positions were randomized upon the completion of baseline testing to an experimental or control group. The experimental group completed a 10-week yoga program prescribed three sessions per week during lunch hour (50 min per session). An experienced instructor led the sessions, which emphasized asanas (postures) and vinyasa (exercises). The primary outcome was the high frequency (HF) power component of HRV. Secondary outcomes included additional HRV parameters, musculoskeletal fitness (i.e. push-up, side-bridge, and sit & reach tests) and psychological indices (i.e. state and trait anxiety, quality of life and job satisfaction).ResultsAll measures of HRV failed to change in the experimental group versus the control group, except that the experimental group significantly increased LF:HF (p = 0.04) and reduced pNN50 (p = 0.04) versus control, contrary to our hypotheses. Flexibility, evaluated via sit & reach test increased in the experimental group versus the control group (p < 0.001). No other adaptations were noted. Post hoc analysis comparing participants who completed ≥70% of yoga sessions (n = 11) to control (n = 19) yielded the same findings, except that the high adherers also reduced state anxiety (p = 0.02) and RMSSD (p = 0.05), and tended to improve the push-up test (p = 0.07) versus control.ConclusionsA 10-week hatha yoga intervention delivered at the office worksite during lunch hour did not improve HF power or other HRV parameters. However, improvements in flexibility, state anxiety and musculoskeletal fitness were noted with high adherence. Future investigations should incorporate strategies to promote adherence, involve more frequent and longer durations of yoga training, and enrol cohorts who suffer from higher levels of work-related stress.Trial registrationACTRN12611000536965

How do patient expectancies, quality of life, and postchemotherapy nausea interrelate?

Increasing evidence suggests a relation between patient expectancies and chemotherapy‐induced nausea. However, this research has often failed to adequately control for other possible contributing factors. In the current study, the contribution of patient expectancies to the occurrence and severity of postchemotherapy nausea was examined using more stringent statistical techniques (namely hierarchical regression) than other similar studies that have relied on bivariate correlations, chi‐square tests, and stepwise regression, and further extended upon previous research by including quality of life (QoL) in the analysis.

Partial reinforcement, extinction, and placebo analgesia

Summary This study provides the first evidence that placebo analgesia can be established via partial reinforcement, and importantly, that these effects are resistant to extinction. ABSTRACT Numerous studies indicate that placebo analgesia can be established via conditioning procedures. However, these studies have exclusively involved conditioning under continuous reinforcement. Thus, it is currently unknown whether placebo analgesia can be established under partial reinforcement and how durable any such effect would be. We tested this possibility using electrocutaneous pain in healthy volunteers. Sixty undergraduates received placebo treatment (activation of a sham electrode) under the guise of an analgesic trial. The participants were randomly allocated to different conditioning schedules, namely continuous reinforcement (CRF), partial reinforcement (PRF), or control (no conditioning). Conditioning was achieved by surreptitiously reducing pain intensity during training when the placebo was activated compared with when it was inactive. For the CRF group, the placebo was always followed by a surreptitious reduction in pain during training. For the PRF group, the placebo was followed by a reduction in pain stimulation on 62.5% of trials only. In the test phase, pain stimulation was equivalent across placebo and no placebo trials. Both CRF and PRF produced placebo analgesia, with the magnitude of initial analgesia being larger after CRF. However, although the placebo analgesia established under CRF extinguished during test phase, the placebo analgesia established under PRF did not. These findings indicate that PRF can induce placebo analgesia and that these effects are more resistant to extinction than those established via CRF. PRF may therefore reflect a novel way of enhancing clinical outcomes via the placebo effect.

Patient Expectancy and Post-chemotherapy Nausea: A Meta-analysis

BackgroundPost-chemotherapy nausea remains a significant burden to cancer patients. While some studies indicate that expecting nausea is predictive of experiencing nausea, there are a number of conflicting findings.PurposeThe purpose of this study was to conduct a meta-analytic review to determine the strength of the relationship between expectancy and post-chemotherapy nausea.MethodsThe findings from 17 relevant studies (n = 2,400) identified through systematic searches of Medline, PsycInfo, and Cinhal were analyzed using a combination of meta-analytic techniques.ResultsOverall, there was a robust positive association between expectancy and post-chemotherapy nausea (ESr = 0.18, equivalent to Cohen’s d = 0.35), suggesting that patients with stronger expectancies experience more chemotherapy-induced nausea. Although weaker associations were found in studies employing multivariate analysis, specifically controlling for a history of nausea, and involving breast cancer patients, none of the moderators assessed were statistically significant.ConclusionsThese findings suggest that patient expectancies may contribute to post-chemotherapy nausea and that expectancy-based manipulations may provide a useful intervention strategy.

Towards a new model of attentional biases in the development, maintenance, and management of pain.

Abstract Individuals with chronic pain demonstrate attentional biases (ABs) towards pain-related stimuli. However, the clinical importance of these biases is yet to be determined and a sound theoretical model for explaining the role of ABs in the development and maintenance of pain is lacking. Within this article, we (1) systematically review prospective and experimental research exploring ABs and pain outcomes in light of current theoretical models and (2) propose a theoretical framework for understanding AB in pain. Across prospective research, an attentional pattern of vigilance–avoidance was observed. Interventions targeting ABs were less consistent; however, there were promising findings among studies that found attentional training effects, particularly for laboratory research. The proposed Threat Interpretation Model suggests a relationship between threat, interpretation, and stimuli in determining attentional processes, which while tentative generates important testable predictions regarding the role of attention in pain and builds on previous theoretical and empirical work in this area.