Types, frequencies, and burden of nonspecific adverse events of drugs: analysis of randomized placebo‐controlled clinical trials

Mahr, Alfred; Golmard, Clara; Pham, E.; Iordache, L.; Deville, Laure; Faure, Pierre

doi:10.1002/pds.4169

Cited by 53 publications

(49 citation statements)

References 36 publications

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“…The direct economic impact of treatment non‐adherence—from unresolved illness and additional medical care—was estimated to cost the Australian health system over $660 million in 2010 (Australian Department of Health and Ageing, ). At a very conservative estimate, 40% of the side effects driving non‐adherence are caused by the nocebo effect (Mahr et al, ). Considering the direct impact on non‐adherence alone, the nocebo effect is costing the Australian health system more than $52 million per year.…”

Section: Discussionmentioning

confidence: 99%

“…Nocebo effects are common and may occur more frequently than side effects caused by the specific pharmacological action of a drug. Mahr et al () compared the side effects reported in the placebo and active drug arms of 234 randomised placebo‐controlled clinical trials. In patients receiving an active drug, 76% reported one or more side effects.…”

Section: The Nocebo Effectmentioning

confidence: 99%

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Nocebo effects in health psychology

Faasse

2019

Australian Psychologist

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The nocebo effect is a potentially powerful phenomenon that can result in harmful or unpleasant treatment outcomes caused by negative expectations, past experience, and other aspects of the treatment context. These aversive outcomes can cause patients to discontinue an otherwise beneficial treatment-resulting in suboptimal health outcomes, added burden of illness, reduced quality of life, and unnecessary hospitalisations, medical consultations, and increased cost for both the patient and the health care system. Much research to date has focused on the role of negative expectations in nocebo effects; this review also emphasises the more overlooked mechanisms of anxiety and classical conditioning, and how these might be usefully targeted to reduce nocebo effects. The evidence for each of these mechanisms, and their potential interactions, is reviewed. Regardless of how they develop, nocebo effects can contribute substantially to the overall burden of treatment side effects, and an overview of evidence-based interventions to reduce nocebo effects by targeting each of the underlying mechanisms is presented. Currently, no strategies are systematically applied to reduce nocebo effects, and most interventions have yet to be translated from experimental laboratory research into applied clinical settings. Future work should focus on developing and testing theoretically-based interventions to reduce nocebo effects, and on translating findings from lab-based studies into clinical practice and healthcare policy. K E Y W O R D S anxiety, classical conditioning, negative expectations, nocebo, side effects

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Section: Discussionmentioning

confidence: 99%

Section: The Nocebo Effectmentioning

confidence: 99%

Nocebo effects in health psychology

Faasse

2019

Australian Psychologist

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“…However, not all side effects are the result of the pharmacological action of a medication. Indeed, it has been suggested that anywhere between 38% and 100% of apparent side effects are caused by other factors (Mahr et al ., 2017). The nocebo effect, defined as the experience of unpleasant or noxious symptoms in response to an inert exposure (Kennedy, 1961), is believed to explain many of these non‐specific side effects (Barsky, Saintfort, Rogers, & Borus, 2002).…”

Section: Introductionmentioning

confidence: 99%

Medicine‐related beliefs predict attribution of symptoms to a sham medicine: A prospective study

Webster

Weinman

Rubin

2018

British J Health Psychol

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ObjectivesTo investigate a range of possible predictors of nocebo responses to medicines.DesignProspective cohort study.MethodsIn total, 203 healthy adult volunteers completed measures concerning demographics, psychological factors, medicine‐related beliefs, baseline symptoms, and symptom expectations before taking a sham pill, described as ‘a well‐known tablet available without prescription’ that was known to be associated with several side effects. Associations between these measures and subsequent attribution of symptoms to the tablet were assessed using a hurdle model consisting of a joint logistic and truncated negative binomial regression.ResultsMen had an increased odds of attributing symptoms to the tablet OR = 1.52, and older participants had decreased odds, OR = 0.97. Medicine‐related beliefs were important, with modern health worries, belief that medicines cause harm and perceived sensitivity to medicines associated with increased odds of symptom attribution, OR = 1.02, 1.10, 1.09, respectively. Trust in medicines and pharmaceutical companies decreased the odds of symptom attribution, OR = 0.91, 0.88, respectively. The number of symptoms at baseline and the expected likelihood of symptoms were associated with an increased odds of attributing symptoms to the tablet, OR = 1.07, 1.06, respectively. Anxiety, previous symptom experience, symptom expectations, and modern health worries were also important in predicting the number of symptoms participants attributed to the tablet.ConclusionIt is hard to predict who is at risk of developing nocebo responses to medicines from demographic or personality characteristics. Context‐specific factors such as beliefs about and trust in medicines, current symptoms and symptom expectations are more useful as predictors. More work is needed to investigate this in a patient sample. Statement of contribution What is already known on this subject? Many patients report non‐specific side effects to their medication which may arise through a nocebo effect.Whether some people are particularly predisposed to experience nocebo effects remains unclear. What does this study add? Demographic and personality characteristics are poor predictors of symptom attribution to a sham medicine.Instead, context‐specific factors that concern people's beliefs surrounding medicines, their current symptoms, and symptom expectations are more useful as predictors of symptom attribution.

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“…Recent evidence indicates that between 40% and 100% of all side effects are caused by "non-specific" factors associated with the treatment context, rather than by the active ingredients in the treatment itself [1]. A large proportion of reported side effects are thought to be due to the nocebo effect: the experience of unpleasant physical symptoms or outcomes in response to an inert agent (e.g., a placebo treatment), caused by psychological mechanisms including negative expectations [2,3].…”

Section: Introductionmentioning

confidence: 99%

The Influence of Social Modeling, Gender, and Empathy on Treatment Side Effects

Faasse

Parkes

Kearney

et al. 2018

Annals of Behavioral Medicine

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Background Social modeling has the capacity to shape treatment outcomes, including side effects. Purpose This study investigated the influence of social modeling of treatment side effects, gender, and participant empathy, on side effects of a placebo treatment. Methods Ninety-six participants (48 females) completed a study purportedly investigating the influence of modafinil (actually placebo) on alertness and fatigue. The participants were randomly seated with a male or female confederate and saw this confederate report experiencing side effects or no side effects. Participant empathy was assessed at baseline. Changes in modeled and general symptoms, and misattribution of symptoms, were assessed during the session and at 24-hr follow-up. Results During the experimental session, seeing side effect modeling significantly increased modeled symptoms (p = .023, d = 0.56) but not general or misattributed symptoms. Regardless of modeling condition, female participants seated with a female model reported significantly more general symptoms during the session. However, response to social modeling did not differ significantly by model or participant gender. At follow-up, the effect of social modeling of side effects had generalized to other symptoms, resulting in significantly higher rates of modeled symptoms (p = .023, d = 0.48), general symptoms (p = .013, d = 0.49), and misattributed symptoms (p = .022, d = 0.50). The experience of modeled symptoms in response to social modeling was predicted by participants' levels of baseline empathy. Conclusions Social modeling of symptoms can increase the side effects following treatment, and this effect appears to generalize to a broader range of symptoms and symptom misattribution over time. Higher baseline empathy seems to increase response to social modeling.

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Types, frequencies, and burden of nonspecific adverse events of drugs: analysis of randomized placebo‐controlled clinical trials

Abstract: The large proportion of nonspecific AEs reported in active-drug recipients of RPCCTs, including serious and drug-related AEs, highlights the limitations of clinical trial data to determine the tolerability of drugs. Copyright © 2017 John Wiley & Sons, Ltd.

Cited by 53 publications

References 36 publications

Nocebo effects in health psychology

Nocebo effects in health psychology

Medicine‐related beliefs predict attribution of symptoms to a sham medicine: A prospective study

The Influence of Social Modeling, Gender, and Empathy on Treatment Side Effects

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