Figure - uploaded by Martina Amanzio
Content may be subject to copyright.
Source publication
The large number of randomized controlled clinical trials on migraine have drawn the attention of some authors to the need to improve the design of such trials. In particular, adequate methodology is a critical issue in their planning and execution, as different methodological approaches can translate into different results. The side-effects observ...
Similar publications
Background Nocebo effects (‘negative placebo’ effects) experienced by clinical trial participants can arise from an underlying condition or through communication about side effects in the participant information leaflets (or elsewhere). However, little is known about how information on potential side effects is provided to trial participants. In th...
Working memory is considered as a core aspect of cognitive function and its impairment in a wide range of mental disorders has resulted in it being considered as an important transdiagnostic feature. To date pharmacological and behavioural strategies for augmenting working memory have achieved only moderate success. Here we have taken a different a...
Citations
... 1) A further natural history group (NH), the so-called 'third arm' of the experimentation, should be added and considered, in order to better study the side effects usually observed in the placebo group, in terms of nocebo effects. This third group would make it possible to study adverse events more accurately, such as the difference between the symptoms collected in the NH group and the side effects presented in the placebo group [11]. As previously noted, the observations achieved through the NH group analysis should be incorporated more frequently into the RCTs, such as in Zelen Design. ...
... Patients characteristics that could represent an important bias factor in the observed results must be evaluated using appropriate assessment scales the presence of: positive symptoms [5,6], mood changes in terms of depression and anxiety, tendency to catastrophize, prior negative experiences with drug treatment, preexisting general medical complaints, and a tendency to somatize, amplify symptoms and show selective attention to bodily sensations [11,13]. Importantly, neuropsychological factors, such as global cognition and executive functions should also be assessed [10,[14][15][16], in order to make an accurate description of the possible presence of mild cognitive impairment. ...
... Importantly, the use of an additional natural history group (as reported in point #1)with patients having the same characteristics as those in the other twoshould be considered in RCTs in order to monitor the natural history of the disease in terms of a three-arm controlled trial. The homogeneity of the three groups should be ascertained by comparing the data concerning the patients and the context in order to prevent the effect of selection bias on reported AEs [10,11,14,17]. ...
... In line with these suggestions, an assessment of the expectancies related to treatment should be better developed to give an objective measure of the individual predisposition ( Younger et al., 2012). With this purpose in mind, using an additional natural history group as the trial's so-called third arm is an important factor that should be considered in RCTs (Amanzio, 2011). As to the third group, it would be possible to study the AEs because of the nocebo effects as the difference between the symptoms collected in the natural history group and the side effects presented in the placebo group (Amanzio, 2011). ...
... With this purpose in mind, using an additional natural history group as the trial's so-called third arm is an important factor that should be considered in RCTs (Amanzio, 2011). As to the third group, it would be possible to study the AEs because of the nocebo effects as the difference between the symptoms collected in the natural history group and the side effects presented in the placebo group (Amanzio, 2011). Indeed, natural course conditions should be incorporated more frequently in RCTs, such as in Zelen Design. ...
Background: Antipsychotic clinical trials use to present adverse events (AEs) for the drug under evaluation to treat schizophrenia. Interestingly, patients who receive the placebo during antipsychotic trials often report several AEs, but little is known about the essence of these negative effects in patients with schizophrenia spectrum disorders (SCD). In the present meta-analysis, we evaluated the relationship between the level of psychiatric symptomatology expressed as Positive and Negative Syndrome Scale (PANSS) scores and the rates of AEs reported in the placebo arms of double-blind clinical trials, for commonly prescribed atypical antipsychotic medications. Methods: We selected 58 clinical trials describing AEs in SCD placebo groups, which compared atypical antipsychotic medications with placebo. A total of 6,301 placebo-treated patients were considered. AE profiles of the class were clusterized using MedDRA classification and analysed using a meta-regression approach. Results: In the placebo arms the proportions of patients with any AE was 66.3% (95% CI: 62.7-69.8%). The proportion of withdrawal of patients treated with placebo because of AEs was 7.2% (95% CI: 5.9-8.4%). Interestingly, the AEs in the placebo arms corresponded to those of the antipsychotic-atypical-medication-class against which the placebo was compared. Namely, using meta-regression analysis we found an association between the level of psychiatric symptomatology measured with PANSS scores and higher AEs reported as nervous system (p = 0.020) and gastrintestinal disorders (p = 0.004). Moreover, the level of a higher psychiatric symptomatology expressed with PANSS scores was also related with higher AEs associated with psychiatric symptoms (p = 0.017). Conclusion: These findings emphasise that the AEs in placebo arms of clinical trials of antipsychotic medications were substantial. Importantly, a higher level of psychiatric symptomatology makes SCD patients more prone to express AEs, thus contributing to possible drop-outs and to a lower adherence to treatments. These results are consistent with the expectation theory of placebo and nocebo effects.
... The observed magnitude of the nocebo effect was small, although its presence was unequivocal. The type of adverse events reported for placebo depends on the specific effects expected for active treatment [10]. It is thus tempting to speculate that the effects of any medical intervention may consist of three components, i.e. the specific pharmacological action, a placebo/ nocebo effect with regard to expectations of specific symptoms and a non-specific placebo/nocebo effect. ...
... In clinical trials, a non-specific effect would be difficult to avoid even by using an adjusted informed consent procedure [9,11]. Thus, our results support the proposal that in order to quantify the true effects of a drug in randomised trials where placebo control is ethically justifiable, the inclusion of a third, notreatment (=natural history) arm should be considered [10]. ...
... With this purpose in mind, using an additional natural history group as the trial's so-called third arm is an important factor that should be considered in RCTs. As to the third group, it would be possible to study the AEs because of the nocebo effects as the difference between the symptoms collected in the natural history group and the side effects presented in the placebo group [17]. Indeed, natural course conditions should be incorporated more frequently in RCTs, such as in Zelen Design. ...
The role of psychosocial context around patient and therapy can be studied through randomized clinical trials. The analysis of the results of clinical trials, and considering the adverse events (AEs) in the placebo groups, provides an important perspective of study for this phenomenon. In double-blind, randomized clinical trials, the side effects reported in placebo-treated groups are not associated with pharmacological treatment, but other factors should be taken into account to explain these symptoms. This phenomenon may be conceptualized as ‘nocebo effects’ relating to negative expectations for treatment outcome, even though a role of prior learning in the form of conditioning with active treatments cannot be excluded. This approach makes it possible to observe how associating the placebo groups with a particular drug can cause specific AEs that are consistent with those observed in the active group. This phenomenon was described in a systematic review that examined placebo AEs in tricyclic antidepressant randomized clinical trials. The authors depicted nocebo effects in antidepressant placebos similar to the AE profiles of the real drugs, which they were matched with. These key findings contrast with the belief that nocebo effects were simply nonspecific. Moreover, they emphasize the need to develop standardized procedures for collecting information about AEs in randomized, double-blind, placebo-controlled trials determining drug efficacy.
... Some authors have made some recommendations to reduce the nocebo effect in RCT's. For instance, Amanzio (2011) have proposed the use of the natural history group as a "third arm" in pain trials, allowing the comparison of placebo groups with non-treated groups in order to seek for specific nocebo symptoms. Moreover, Cohen (2014) has proposed new approaches in the informed consent of trials that aim to avoid the nocebo influence due the advertisement of potential adverse events. ...
To compare the incidence of adverse events between active and placebo arms of randomized clinical trials in depressive children and adolescents (C&A) with antidepressant treatments, in order to look for similarities in both groups that allow to establish a possible nocebo effect.
Systematic search strategy (January 1974-March 2013) in electronic databases, conference abstracts, and reference list of systematic reviews and included studies to identify parallel randomized placebo-controlled trials of antidepressants in C&A (<19 years) with major depressive disorder, and one or more interventions of any orally administered antidepressant. The pooled adverse events were calculated based on a fixed-effect model and statistical analysis involved the risk ratio (RR) of adverse events, with 95% confidence intervals (95% CI).
Sixteen studies were included in the review, of which seven studies with a sample of 1911 patients had data to include in the meta-analysis. There was similar risk for the incidence of adverse events between non-active and active group (global RR 1.04, 95% CI: 0.97-1.11).
Depressive C&A allocated to placebo or active group had similar risk to develop adverse events. These similarities in both groups are attributed to the nocebo effect. It is of note that defining "nocebo" effects is challenging in clinical populations because adverse effects may be attributed to the intervention or may be manifestation of the disease itself. The inclusion of a no-treatment arm may be warranted. Nocebo effects are likely when adverse events of placebo mimic the adverse events of active treatment, as was the case here.
... Compared with placebo research, little attention has been directed to clinical studies of nocebo effects and their implications for clinical practice [1]. The nocebo effects analyzed in this meta-analysis represent the effects which can be attributed to a nocebo treatment (i.e., an inert treatment along with verbal suggestions of pain increase) compared with a no-treatment group or condition. ...
The investigation of nocebo effects is evolving and a few literature reviews have emerged, however, so far without quantifying such effects. This quantitative systematic review investigated nocebo effects in pain. We searched the databases PubMed, EMBASE, Scopus, and the Cochrane Controlled Trial Register with the term "nocebo". Only studies that investigated nocebo effects as the effects that follow the administration of an inert treatment along with verbal suggestions of symptom worsening and that included a no-treatment control condition were eligible. Ten studies fulfilled the selection criteria. The effect sizes were calculated using Cohen's d and Hedges' g. The overall magnitude of the nocebo effect was moderate to large (lowest g = 0.62 (0.24-1.01) and highest g = 1.03 (0.63-1.43)) and highly variable (range of g = -0.43-4.05). The magnitudes and range of effect sizes was similar to those of placebo effects (d = 0.81) in mechanistic studies. In studies where nocebo effects were induced by a combination of verbal suggestions and conditioning, the effect size was larger (lowest g = 0.76 (0.39-1.14) and highest g = 1.17 (0.52-1.81)) than in studies where nocebo effects were induced by verbal suggestions alone (lowest g = 0.64 (-0.25-1.53) and highest g = 0.87 (0.40-1.34)). These findings are similar to those in the placebo literature. Since the magnitude of the nocebo effect is variable and sometimes large, this systematic review demonstrates the importance of minimizing nocebo effects in clinical practice.
... The need to measure patient expectancies may be particularly important in the context of clinical trials, where expectancies can blur the distinction between real and placebo conditions [21][22][23][24]. It is also important, given the large percentage of patients who report adverse side effects from sham treatments [21,25,26], to be able to identify the degree to which expectancy contributes to the occurrence of adverse events. ...
Background:
A patient's response to treatment may be influenced by the expectations that the patient has before initiating treatment. In the context of clinical trials, the influence of participant expectancy may blur the distinction between real and sham treatments, reducing statistical power to detect specific treatment effects. There is therefore a need for a tool that prospectively predicts expectancy effects on treatment outcomes across a wide range of treatment modalities.
Purpose:
To help assess expectancy effects, we created the Stanford Expectations of Treatment Scale (SETS): an instrument for measuring positive and negative treatment expectancies. Internal reliability of the instrument was tested in Study 1. Criterion validity of the instrument (convergent, discriminant, and predictive) was assessed in Studies 2 and 3.
Methods:
The instrument was developed using 200 participants in Study 1. Reliability and validity assessments were made with an additional 423 participants in Studies 2 and 3.
Results:
The final six-item SETS contains two subscales: positive expectancy (α = 0.81-0.88) and negative expectancy (α = 0.81-0.86). The subscales predict a significant amount of outcome variance (between 12% and 18%) in patients receiving surgical and pain interventions. The SETS is simple to administer, score, and interpret.
Conclusion:
The SETS may be used in clinical trials to improve statistical sensitivity for detecting treatment differences or in clinical settings to identify patients with poor treatment expectancies.
... We recently demonstrated that informing subjects about the AEs that they may possibly experience could have a significant impact on their actual experience and report of AEs (Amanzio et al., 2009). This phenomenon can be observed not only in the active group but also in the placebo group of RCTs (for a review, see Amanzio, 2011). Although the underlying mechanisms of this phenomenon remain unclear, the nocebo effect may offer an important theoretical framework to interpret the obtained data (Amanzio et al., 2009; Rief et al., 2009). ...
In randomized clinical trials, adverse events (AEs) are reported for the drug under evaluation and compared with the placebo group. Patients who receive placebo treatment report a high frequency of AEs, but little is understood about the nature of these. No study has yet analyzed the level of cognitive impairment as a crucial aspect for the AEs reported by patients.
The rates of AEs reported by patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) in the placebo arms of donepezil trials were compared using a systematic review approach. PubMed was searched with the terms "MCI and donepezil" as well as "AD and donepezil" from January 1989 to December 2010. Nineteen studies fulfilled the selection criteria (3 MCI, n = 783; 16 AD, n = 2,059).
An overall comparison of 81 categories of AEs in the placebo arm of MCI versus AD trials showed that patients in AD trials experienced a significantly higher number of AEs than patients in MCI trials (p < 0.001).
This is the first study showing that AD patients may be at a greater risk of developing AEs than MCI patients. This may be related to a greater presence of somatic comorbidity predisposing them to express emotional distress as physical symptoms and/or to AD patients being frailer and therefore more susceptible to AEs. The phenomena we observed may be interpreted in terms of the "nocebo effect".
... We hypothesized that the effect observed may specifically depend on the patient's and/or investigator's expectations regarding the occurrence of negative symptoms, in terms of a nocebo effect. These nocebo phenomena may help us better understand the occurrence of psychologically driven adverse symptoms, as well as to improve clinical trial designs and patient-provider communication [60]. ...
The psychosocial context surrounding the patient and the psychobiological model do offer interesting perspectives from which to study the placebo response. The term ‘response’ should only be reserved for an active neurobiological process that occurs as a result of a dummy treatment. The context surrounding the administration of a placebo can also lead individuals to expect a worsening of symptoms; indeed changes in the negative direction are observed as part of the nocebo effect. One way of studying nocebo effects after medical treatment is to analyse the findings of randomised double-blind placebo-controlled trials. The importance of these studies is given by their attempt to maximise the placebo components of therapies and thus to minimise the worsening of symptoms. Assessing situations where loss of placebo mechanisms may require increased therapeutic dosage represents another crucial aspect. These aspects become even more important in patients with dementia, who may exhibit a disruption of the expectancy-evoked placebo–analgesia network and impaired sensory and affective responses to pain. In this chapter we attempt to answer specific questions with regard to patients with cognitive impairment, even though at present we only have a limited understanding of the factors that influence patients’ response to pain and to placebo treatment.
