Expectancies in Double-Blind Randomised Placebo-Controlled Trials and Placebo-Induced Side Effects

The majority of research on the placebo effect has focused on beneficial effects in patients or participants told to expect an active treatment, but who are actually given a placebo. Two important and relatively understudied aspects of the placebo effect are the extent to which expectancies influence outcomes in double-blind randomised placebo-controlled trials (RCTs) and whether the placebo effect contributes to treatment side effects. The current project investigated these two issues in both clinical and experimental settings. The first study involved reanalysing a double-blind RCT of naltrexone and acamprosate for alcohol dependence based on whether participants believed they had been allocated to receive active treatment or placebo (perceived treatment). The second study extended on this by developing an experimental model for these effects using dummy (placebo only) double-blind RCTs for cognitive performance. This allowed for the manipulation of observable changes in the form of false feedback. The third study investigated whether warning participants about side effects increases their occurrence, frequency, and/or severity in three dummy trials for sleep difficulty in healthy volunteers. The final study complemented this by examining whether first time chemotherapy patients’ expectancies for nausea were associated with their post-chemotherapy nausea. The studies on perceived treatment in double-blind RCTs indicated that participants’ beliefs about their treatment allocation can influence their actual treatment outcomes via the placebo effect and that these beliefs are affected by the feedback they receive about their performance. The studies on placebo-induced side effects indicated that the placebo effect may contribute to treatment side effects but that this effect is generally likely to be small. These findings confirm that the placebo effect can influence treatment outcomes and emphasise the importance of considering patient expectancies when delivering medical treatment. They also highlight some general limitations associated with research on the placebo effect, which include, whether conveying uncertainty undermines the placebo effect and whether measuring or manipulating expectancies is the best way to evaluate the placebo effect

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

The effect of threat on cognitive biases and pain outcomes: an eye-tracking study

Background: Theoretical accounts of attentional and interpretation biases in pain suggest that these biases are interrelated and are both influenced by perceived threat. A laboratory-based study was conducted to test whether these biases are influenced by threat, their interrelationship, and whether attention or interpretation biases predict pain outcomes. Methods: Healthy participants (n=87) received either threatening or reassuring pain information, and then completed questionnaires, interpretation and attentional bias tasks (with eye-tracking), and a pain task (the cold pressor). Results: There was an interaction effect for threat group and stimuli type on mean dwell time for face stimuli, such that there was an attentional bias towards happy faces in the low but not high threat group. Further, high threat was also associated with shorter pain tolerance, increased pain, and distress. In correlational analyses, avoidance of affective pain words was associated with increased pain. However, no relationship was found between attention and interpretation biases, and interpretation biases were not influenced by threat or associated with pain. Conclusions: These findings provide partial support for the threat interpretation model and the importance of threat and affective pain biases, yet no relationship between cognitive processing biases was found, which may only occur in clinical pain samples

Attentional bias modification and pain: The role of sensory and affective stimuli

There is growing evidence to support attentional bias modification (ABM) techniques such as the modified dot-probe task within the pain literature. Such techniques can help to inform theoretical models of pain by identifying the causal role of attentional bias constructs. The aim of this research was to explore the effects of dot-probe ABM that trains individuals towards (+) or away from (-) sensory (S) and affective (A) pain words, on attentional biases, interpretation biases, and pain outcomes. Healthy undergraduate students (N= 106) completed questionnaires, an attentional bias dot-probe task, and an interpretation bias task before and after ABM, one of four ABM versions that differed in training direction (S+A+, S-A+, S+A-, S-A-), and pain outcomes using the cold pressor task. Those trained towards affective pain words were found to have a greater pain threshold but also greater distress at tolerance. However, mechanisms of change could not be established, as ABM did not affect attentional or interpretation bias, even though changes in attentional bias were associated with pain outcomes. These findings provide partial support for the threat interpretation model and highlight the utility of affective pain ABM, although further investigation of causal mechanisms is warranted

Placebo caffeine reduces withdrawal in abstinent coffee drinkers

Background: Expectancies have been shown to play a role in the withdrawal syndrome of many drugs of addiction. However no studies have examined the effects of expectancies across a broad range of caffeine withdrawal symptoms, including craving. Aims: The purpose of the current study was to use caffeine as a model to test the effect of expectancy on withdrawal symptoms, specifically whether the belief that one has ingested caffeine is sufficient to reduce caffeine withdrawal symptoms and cravings in abstinent caffeine drinkers. Methods 24-h abstinent regular coffee drinkers completed the Caffeine Withdrawal Symptom Questionnaire (CWSQ) before and after receiving decaffeinated coffee. Half the participants were led to believe the coffee was regular caffeinated coffee (Told group) and half were told that it was decaffeinated (Low Expectancy group). Results: Participants in the High Expectancy group reported a significantly greater reduction in craving, fatigue, lack of alertness and flu-like feelings factors of the CWSQ than those in the Low Expectancy. Conclusions: These results indicate that the belief that one has consumed caffeine can affect caffeine withdrawal symptoms, especially craving, even when no caffeine has been consumed

Nocebo Hyperalgesia, Partial Reinforcement, and Extinction

Many studies have found evidence of conditioning-induced nocebo hyperalgesia. However, these studies have exclusively involved continuous reinforcement schedules. Thus, it is currently unknown whether nocebo hyperalgesia can result following partial reinforcement. We tested this using electrodermal pain stimulation in healthy volunteers. Undergraduates (n=135) received nocebo treatment under the guise of a hyperalgesic. Participants were randomly allocated to continuous reinforcement (CRF), partial reinforcement (PRF), or control (no conditioning). Conditioning involved surreptitiously increasing pain stimulation on nocebo trials relative to control trials. During training, the CRF group always had the nocebo paired with the surreptitious pain increase, whereas the PRF group only experienced the increase on 62.5% of nocebo trials. In the test phase, pain stimulation was equivalent across nocebo and control trials. Partial reinforcement was sufficient to induce nocebo hyperalgesia, however, this was weaker than continuous reinforcement. Interestingly, nocebo hyperalgesia failed to extinguish irrespective of the training schedule. Additional assessment of expectancies indicated strong concordance between these and nocebo hyperalgesia. Overall, these findings suggest that once established, nocebo hyperalgesia may be difficult to disrupt. As such, partial reinforcement may be one method of reducing the intensity of nocebo hyperalgesia in the clinic, which may be particularly important given its persistence. Perspectives: This study provides novel evidence that partial reinforcement results in weaker nocebo hyperalgesia than continuous reinforcement and that nocebo hyperalgesia fails to extinguish, irrespective of the training schedule. As a result, partial reinforcement may serve as a method for reducing the intensity of nocebo hyperalgesia in the clinic

Latent Inhibition Reduces Nocebo Nausea, Even Without Deception

Background: Nocebo nausea is a debilitating and prevalent side effect that can develop after conditioning occurs between cues present in the treatment context and the experience of nausea. Interventions that retard conditioning may therefore be able to reduce nocebo nausea. Purpose: To test whether ‘latent inhibition’, where pre-exposing cues in the absence of an outcome retards subsequent learning about those cues, could reduce nocebo nausea in healthy adults. Methods: We examined this possibility using a Galvanic Vestibular Stimulation (GVS) model of nausea in healthy participants, with pre-exposure to the treatment cues achieved using a placebo version of GVS. Results: In Experiment 1 we found clear evidence of conditioned nocebo nausea that was eradicated by latent inhibition following pre-exposure to placebo stimulation. Experiment 2 tested whether deception, which may be unethical in clinical settings, was necessary to produce latent inhibition by including an open pre-exposure group informed they were pre-exposed to placebo stimulation. Experiment 2 replicated the latent inhibition effect on nocebo nausea following deceptive pre-exposure from Experiment 1 and found that open pre-exposure was just as effective for reducing nocebo nausea. In both experiments, there was an interesting discrepancy found in expectancy ratings whereby expectations appeared to drive the development of conditioned nocebo nausea, but were not responsible for its retardation through latent inhibition. Conclusions: These findings have significant clinical implications. Applying open pre-exposure in clinical settings may effectively and ethically reduce the development of nocebo effects for nausea and other conditions via latent inhibition

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, Parkinson’s disease, and some surgical procedures. Here, we review pioneering studies and recent advances in behavioural, neurobiological, and genetic influences on the placebo effect. Based on a previous developed conceptual framework, the placebo effect is presented as the product of a general expectancy learning mechanism in which verbal, conditioned, observational, and social cues are centrally integrated to change behaviours 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 using well-established behavioral paradigms have identified key brain regions and modulatory mechanisms underlying placebo effects. 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 behavioural, 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 maximise treatment outcomes in clinical settings

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, Parkinson’s disease, and some surgical procedures. Here, we review pioneering studies and recent advances in behavioural, neurobiological, and genetic influences on the placebo effect. Based on a previous developed conceptual framework, the placebo effect is presented as the product of a general expectancy learning mechanism in which verbal, conditioned, observational, and social cues are centrally integrated to change behaviours 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 using well-established behavioral paradigms have identified key brain regions and modulatory mechanisms underlying placebo effects. 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 behavioural, 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 maximise treatment outcomes in clinical settings

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 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\u3c0.05). Respiration rate was reduced during yoga and meditation versus control (P\u3c0.05). 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\u3c0.05). 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