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 suppression 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 impact of side effect framing on COVID-19 booster vaccine intentions in an Australian sample.

OBJECTIVE: To evaluate the effect of presenting positively attribute-framed side effect information on COVID-19 booster vaccine intention relative to standard negatively-framed wording and a no-intervention control. DESIGN AND PARTICIPANTS: A representative sample of Australian adults (N = 1204) were randomised to one of six conditions within a factorial design: Framing (Positive; Negative; Control) × Vaccine (Familiar (Pfizer); Unfamiliar (Moderna)). INTERVENTION: Negative Framing involved presenting the likelihood of experiencing side effects (e.g., heart inflammation is very rare, 1 in every 80,000 will be affected), whereas Positive Framing involved presenting the same information but as the likelihood of not experiencing side effects (e.g., 79,999 in every 80,000 will not be affected). PRIMARY OUTCOME: Booster vaccine intention measured pre- and post-intervention. RESULTS: Participants were more familiar with the Pfizer vaccine (t(1203) = 28.63, p <.001, Cohen's dz = 0.83). Positive Framing (M = 75.7, SE = 0.9, 95% CI = [73.9, 77.4]) increased vaccine intention relative to Negative Framing (M = 70.7, SE = 0.9, 95% CI = [68.9, 72.4]) overall (F(1, 1192) = 4.68, p =.031, ηp2 = 0.004). Framing interacted with Vaccine and Baseline Intention (F(2, 1192) = 6.18, p =.002, ηp2 = 0.01). Positive Framing was superior, or at least equal, to Negative Framing and Control at increasing Booster Intention, irrespective of participants' pre-intervention level of intent and vaccine type. Side effect worry and perceived severity mediated the effect of Positive vs. Negative Framing across vaccines. CONCLUSION: Positive framing of side effect information appears superior for increasing vaccine intent relative to the standard negative wording currently used. PRE-REGISTRATION: See: aspredicted.org/LDX_2ZL.

A comparison of the FACT-G and the Supportive Care Needs Survey (SCNS) in women with ovarian cancer: unidimensionality of constructs.

PURPOSE: Health-related quality of life (HRQoL) and unmet needs (needs) questionnaires offer alternative perspectives for assessing cancer patients' concerns. We examined whether the conceptual differences underlying these alternative approaches yield corresponding empirical differences. METHODS: Eight-hundred and seventy-four women with ovarian cancer completed the Functional Assessment of Cancer Therapy scale (FACT-G; HRQoL) and the Supportive Care Needs Survey (SCNS-SF34; needs) every 3 months for 2 years. Correlational analysis, exploratory and confirmatory factor analysis (EFA/CFA), and Rasch analysis tested the relationship between patients' responses to similar domains and similar items across the two questionnaires. RESULTS: Strong correlations were found between items with virtually identical wording (0.67-0.75), while moderate to strong correlations (0.55-0.65) were found for those with very similar wording. EFA identified two common domains across the two questionnaires: physical and psychological. For each common domain, CFA indicated models involving a single construct with systematic variation within each questionnaire fit best. Rasch analysis including very similar items within the physical and psychological domains (separately) demonstrated strong evidence of unidimensionality. CONCLUSIONS: The high degree of similarity between patient responses to items addressing the same or very similar concerns suggests either that HRQoL and needs approaches do not reflect different constructs or that patients may not be able to differentiate between the severity of a concern and the level of need associated with that concern, especially when these are assessed in quick succession.

Pre-Exposure, But Not Overshadowing, Inhibits Nocebo Hyperalgesia.

Nocebo hyperalgesia is a pervasive problem that significantly adds to the burden of pain. Conditioning is a key mechanism of nocebo hyperalgesia and recent evidence indicates that, once established, nocebo hyperalgesia is resistant to extinction. This means that preventive strategies are critical. We therefore tested whether two novel strategies - overshadowing (Experiment 1) and pre-exposure (Experiment 2) - could inhibit conditioned nocebo hyperalgesia. Overshadowing involves introducing additional cues during conditioning that should compete with and overshadow learning about the target nocebo cue. Pre-exposure involves pre-exposing the target nocebo cue in the absence of pain, which should diminish its ability to become associated with pain later. In both studies, healthy volunteers (N = 141) received exposure to a series of electrocutaneous pain stimuli with and without a sham electrode 'activated', which they were led to believe was a genuine hyperalgesic treatment. Nocebo conditioning was achieved by pairing sham activation with high pain prior to testing at equivalent pain intensity. In both studies, standard nocebo conditioning led to clear nocebo hyperalgesia relative to natural history controls. In Experiment 1, there was no evidence that overshadowing attenuated nocebo hyperalgesia. Importantly, however, Experiment 2 found that pre-exposure successfully attenuated nocebo hyperalgesia with post hoc analysis suggesting that this effect was dose-dependent. These findings provide novel evidence that pre-exposure, but not overshadowing, could be a cheap and effective way for mitigating the substantial harm caused by conditioned nocebo hyperalgesia in clinical settings. PERSPECTIVE: Nocebo hyperalgesia causes substantial patient burden with few preventive options available. Our study found novel evidence that pre-exposing treatment cues without pain, but not overshadowing them with other cues, has the capacity to inhibit conditioned nocebo hyperalgesia. Pre-exposure may therefore be an effective preventive strategy to combat nocebo hyperalgesia.

Deceptive but not open label placebos attenuate motion-induced nausea.

OBJECTIVE: Nausea is a common complaint, known to respond to the placebo effect. Existing research has employed deception when administering placebos for nausea, limiting therapeutic translation on ethical grounds. We therefore examined the potential of non-deceptive open-label placebos (OLPs) to reduce nausea. METHODS: Galvanic Vestibular Stimulation (GVS) and Virtual Reality (VR) were employed to model nausea in healthy volunteers across two experiments. In both experiments nausea was elicited with and without sham treatment (peppermint vapor and brain stimulation, respectively). In Exp. 1, participants (n = 61) were randomized to deceptive placebo, semi-open placebo, fully-open placebo, or control. In Exp. 2, participants (n = 93) were randomized to deceptive placebo, semi-open placebo, or control. RESULTS: Exp. 1 found limited evidence for a placebo effect (F(1, 56) = 1.15, p = .29, ηp2 =0.02), even following deceptive treatment (F(1, 56) = 1.92, p = .17, ηp2=0.03). In Exp. 2, deceptive placebo reduced nausea relative to control (F(1, 89) = 6.91, p = .010, ηp2=0.07) and OLP (F(1, 89) = 5.47, p = .022, ηp2=0.06). Pooled Bayesian analysis across experiments provided strong evidence that deceptive placebos reduce nausea relative to control (BF10 = 30.91) and anecdotal evidence for the benefit of deceptive treatment over non-deceptive (BF10 = 2.46) and no benefit of OLP over control (BF10 = 0.63). CONCLUSIONS: No positive evidence for OLP effects in nausea were observed. However, a deceptive effect in VR was observed. These findings raise questions regarding the efficacy of open-label intervention in nausea.

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 and 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. WHAT DOES THIS STUDY ADD?: In healthy participants, no relationship between attention and interpretation biases was found. Eye tracking revealed an association between later attentional processes and pain. Threat influenced attentional biases and pain outcomes, partially supporting theoretical accounts.

Galvanic Vestibular Stimulation: a new model of placebo-induced nausea.

OBJECTIVE: Traditional rotation-based models of placebo nausea are limited because they do not have vehicle settings and are tied to their context. The present study introduces a new model for examining placebo-induced nausea in the laboratory that overcomes these limitations, namely, Galvanic Vestibular Stimulation (GVS). GVS stimulates the vestibular system to cause nausea through sensory mismatch with visual cues and importantly has a non-nauseating placebo setting. Using this, we tested whether conditioning could elicit placebo nausea when participants were later exposed to placebo stimulation as well as whether this placebo nausea was generalised across contexts--something that is extremely difficult to test with rotation-based models of placebo nausea. METHODS: Thirty healthy undergraduate students were randomised to receive either placebo GVS (controls) or active GVS during training (Context-Consistent and Context-Change). On test, all groups received placebo GVS. The controls and Context-Consistent groups were tested in the same context as training, whereas the Context-Change group was tested in a new context. RESULTS: Participants conditioned with nausea during training had significantly higher nausea symptom ratings after placebo stimulation on test than those given no conditioning. This placebo-induced nausea also generalised to a novel test context with no differences observed between the Context-Change and Context-Consistent groups. CONCLUSION: GVS provides a new model of placebo-induced nausea that overcomes limitations to traditional rotation-based paradigms. Future studies should use this device to explore the effect of instructions and conditioning on the development of placebo nausea and to assess the efficacy of conditioning-based interventions for clinical use.

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 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.