It is not just the drugs that matter: the nocebo effect

Wojtukiewicz, Marek Z.; Polityńska, Barbara; Skalij, Piotr; Tokajuk, Piotr; Wojtukiewicz, Anna M.; Honn, Kenneth V.

doi:10.1007/s10555-019-09800-w

Cited by 12 publications

(7 citation statements)

References 93 publications

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“…The nocebo effect refers to the phenomenon that negative expectations of patients have a negative effect on the outcome. 19 A clear majority of patients in this study indicated at their final visit that they received placebo, including half of patients from the IVIg continuation group who remained stable during the trial period, both supporting this hypothesis of nocebo effect. This is in line with a recent systematic review that showed a considerable nocebo effect in CIDP trials, especially when using non-deterioration as the primary end point.…”

Section: Discussionsupporting

confidence: 60%

Withdrawal of intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy

Adrichem

Lucke

Vrancken

et al. 2022

Brain

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Intravenous immunoglobulins (IVIg) are an efficacious treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Biomarkers for disease activity are lacking, making the need for ongoing treatment difficult to assess, leading to potential overtreatment, and high health care costs. Our objective was to determine whether IVIg withdrawal is non-inferior to continuing IVIg treatment and to determine how often patients are overtreated. We performed a randomized, double-blind, IVIg-controlled non-inferiority trial in seven centers in the Netherlands. Adults with clinically stable CIDP using IVIg maintenance treatment for at least 6 months were included. Patients received either IVIg withdrawal (placebo) as investigational treatment or continuation of IVIg treatment (control). The primary outcome was the mean change in logit scores from baseline to 24-weeks follow-up on the patient-reported Inflammatory Rasch-Overall Disability Scale (iRODS). The non-inferiority margin was predefined as between-group difference in mean change scores of -0.65. Patients who deteriorated could reach a relapse endpoint according to predefined criteria. Patients with a relapse endpoint after IVIg withdrawal entered a restabilization phase. All patients from the withdrawal group who remained stable, were included in an open-label extension phase of 52 weeks. We included 60 patients of whom 29 were randomised to IVIg withdrawal and 31 to continuation of treatment. The mean age was 58 years (SD 14.7) and 67% was male. The between-group difference in mean change iRODS scores was -0.47 (95%CI -1.24 to 0.31), indicating that non-inferiority of IVIg withdrawal could not be established. In the IVIg withdrawal group, 41% remained stable for 24 weeks, compared to 58% in the IVIg continuation group (-17%; 95%CI -39 to 8). Of the IVIg withdrawal group, 28% remained stable at end of the extension phase. Of the patients in the restabilization phase, 94% restabilized within 12 weeks. In conclusion, it remains inconclusive whether IVIg withdrawal is non-inferior compared to continuing treatment, partly due to larger than expected confidence intervals leading to an underpowered study. Despite these limitations, a considerable proportion of patients could stop treatment and almost all patients who relapsed were restabilized quickly. Unexpectedly, a high proportion of IVIg treated patients experienced a relapse endpoint, emphasizing the need for more objective measures for disease activity in future trials, as the patient reported outcome measures might not have been able to identify true relapses reliably. Overall, this study suggests that withdrawal attempts are safe and should be performed regularly in clinically stable patients.

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Section: Discussionsupporting

confidence: 60%

Withdrawal of intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy

Adrichem

Lucke

Vrancken

et al. 2022

Brain

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“…45 This may be attributed to the patient's expectation of adverse drug reactions, which leads to overmonitoring of their physical status. 46 Meanwhile, differences in the research design (eg, the content and manner of disclosure) and prior patient history of adverse pharmaceutical reactions might impact patient's expectations. 47 Therefore, researchers shall appropriately expose patients to information about the drug or explain how the nocebo effect works to mitigate patients' expectations of AEs.…”

Section: Discussionmentioning

confidence: 99%

Nocebo response intensity and influencing factors in the randomized clinical trials of functional dyspepsia: A systematic review and meta‐analysis

Feng

Zhang

et al. 2023

J of Digest Diseases

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ObjectiveThe nocebo effect, a phenomenon that pertains to the negative impacts experienced by patients due to their negative expectations, is not connected to the physiological mechanism of the treatment in question. Our article aims to evaluate the degree of the nocebo response in patients with functional dyspepsia and explore its influencing factors.MethodsThe researchers searched Embase, Pubmed and Cochrane Library databases through March 2021, including randomized, parallel‐designed, placebo‐controlled trials examining pharmacological interventions for patients with functional dyspepsia. Our study involved conducting a meta‐analysis that utilized random effects to analyze the proportion of adverse events among participants who were administered placebos. We aimed to investigate the correlation between trial characteristics and the magnitude of the nocebo effect response rate.ResultsUpon thorough research and scrutiny of various databases, a staggering 8,076 studies were identified for further analysis. After an assessment, 27 studies were deemed eligible and included in our analysis. The total nocebo response rate was 27% (95% CI: 18–37%). The most frequently reported adverse events were nasopharyngitis (9%), constipation (6%), headache (5%) and diarrhoea (3%). The nocebo response rate in the international combination trials was higher than that in the Asian trials, higher in the twice‐daily than that in the three‐time‐daily dose and higher in the anti‐vomit drugs than that in the acid inhibitors.DiscussionPatients with functional dyspepsia exhibit notable nocebo response strength in clinical trials. Therefore, we propose researchers adopt a more careful approach when analyzing the relationships between everyday adverse events and interventions administered in such trials.This article is protected by copyright. All rights reserved.

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“…Nocebo-related adverse effects are prevalent in antidepressant studies (Mitsikostas et al estimated 44.7%, while a more recent study by Dodd et al quoted 63.7%) (30, 31). In antidepressant studies, patterns of nocebo-related adverse effects closely resemble adverse effects occurring in the active group (29–33). A meta-analysis by Rief et al demonstrated that significantly greater tolerance of selective serotonin reuptake inhibitors (SSRIs) when compared to tricyclic antidepressants (TCAs) was identical in both groups, those receiving placebo and active treatment alike (34).…”

Section: The True Role Of Expectation-related Placebo Effect In Antidmentioning

confidence: 96%

“…Although underlying mechanisms of placebo and nocebo effects only partially overlap, it seems that the nocebo effect is mostly driven by negative expectation and learning (such as symptom misattribution, social transmission, etc.) (5, 28, 29). Nocebo-related adverse effects are prevalent in antidepressant studies (Mitsikostas et al estimated 44.7%, while a more recent study by Dodd et al quoted 63.7%) (30, 31).…”

Section: The True Role Of Expectation-related Placebo Effect In Antidmentioning

confidence: 99%

Significance of Participants’ Expectations in Managing the Placebo Effect in Antidepressant Research

Ćurković

2019

Front. Psychiatry

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It is not just the drugs that matter: the nocebo effect

Cited by 12 publications

References 93 publications

Withdrawal of intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy

Withdrawal of intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy

Nocebo response intensity and influencing factors in the randomized clinical trials of functional dyspepsia: A systematic review and meta‐analysis

Significance of Participants’ Expectations in Managing the Placebo Effect in Antidepressant Research

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