259 General discussion 8 studied in children, but in adults complex neurobiological reactions, molecular events and neural network changes have been described to be involved.67 For example, placebo analgesia has been shown to be associated with the release of endogenous opioids.68,69 It is conceivable, that both hydrocortisone and placebo induce a similar neurobiological effect, independent of the MR binding effect. Such a neurobiological effect of both hydrocortisone and placebo may also have been mediated by expectancies of parents and children, which are an important learning mechanism and often steer placebo-effects.70 Not all children were aware of the possible beneficial effect due to their young age, and since all our assessments were proxyreported, a placebo-effect by proxy could have occurred: parents who expect their child to improve during the study would experience such an improvement.71,72 Classical conditioning may have played a role as well: by adding an oral suspension to standard treatment, patients can be triggered to show physiological responses to additional medication.67,73,74 Another mechanism, which probably increased the placebo-effect, is the participation effect: through attention and (frequent) contact during participation in a clinical study, a general positive effect can be obtained.75 In our study, the research physician contacted all parents at extra time points, after each dexamethasone course. Parents were asked about adverse events, but they could also talk about encountered problems during the dexamethasone course. Even though no improvement in parental distress was observed, asking parents every dexamethasone course about their child’s behavior, may have made them more perceptible to their child. This can cause adjustment of parental behavior towards the child, which in turn can yield children to behave differently, as previously reported in children with autism.76 Nocebo-effect Substantially more patients (67%) experienced clinically relevant dexamethasone-induced neurobehavioral and sleep problems than in our previous DexaDays-1 study (33%).5 The side effects of dexamethasone are widely known and parents and patients are currently informed extensively about the severity of potential problems, even before they exist. Previous negative experiences, worrisome information, mistaken beliefs and negative expectations induced by verbal suggestions are known to increase or even cause side effects, and are described as nocebo-effects.67,77,78 It is plausible that this noceboeffect (by proxy)71 of dexamethasone played an important role in our findings and even contributed to the pronounced observed placebo-effect. The increased emphasis on providing comprehensive, regular and extensive information about the side effects of dexamethasone, driven by a genuine desire to prioritize psychological well-being, may have inadvertently led to a nocebo-effect experienced by patients and parents at our recently established national pediatric cancer center. This unintended consequence could be attributed to heightened awareness and concerns surrounding potential negative effects, impacting their perceptions and experiences.
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