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White Rose Research Online URL for this paper:
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Version: Accepted Version
Article:
Webster, R.K. orcid.org/0000-0002-5136-1098, Weinman, J. and Rubin, G.J. (2016) A
systematic review of factors that contribute to nocebo effects. Health Psychology, 35 (12).
pp. 1334-1355. ISSN 0278-6133
https://doi.org/10.1037/hea0000416
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A systematic review of factors that contribute to nocebo effects
Rebecca K. Webster, John Weinman, and G. James Rubin
King’s College London
Author note
Rebecca. K Webster, King's College London, Department of Psychological Medicine,
Weston Education Centre, United Kingdom
John Weinman, King’s College London, Institute of Pharmaceutical Science, Franklin-
Wilkins Building, United Kingdom
G. James Rubin, King's College London, Department of Psychological Medicine, Weston
Education Centre, United Kingdom
The research was funded by the National Institute for Health Research Health Protection
Research Unit (NIHR HPRU) in Emergency Preparedness and Response at King’s College
London in partnership with Public Health England (PHE). The views expressed are those of
the authors and not necessarily those of the NHS, the NIHR, the Department of Health or
Public Health England.
Correspondence concerning this article should be addressed to Rebecca. K Webster,
Department of Psychological Medicine, Weston Education Centre, Cutcombe Road, London
SE5 9RJ, UK. E-mail: rebecca.webster@kcl.ac.uk
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Abstract
Objectives: Medication side effects are common, often leading to reduced quality of life, non-
adherence and financial costs for health services. Many side effects are the result of a
psychologically-mediated ‘nocebo effect’. This review identifies the risk factors involved in
the development of nocebo effects.
Methods: Web of Science, Scopus, Medline, PsychINFO, Journals @ Ovid full text, and
Global health were searched using the terms “nocebo” and “placebo effect”. To be included,
studies must have exposed people to an inert substance and have assessed one or more
baseline or experimental factor(s) on its ability to predict symptom development in response
to the inert exposure.
Results: 89 studies were included, 70 used an experimental design and 19 used a prospective
design, identifying 14 different categories of risk factor. The strongest predictors of nocebo
effects were a higher perceived dose of exposure, explicit suggestions that the exposure
triggers arousal or symptoms, observing people experiencing symptoms from the exposure,
and higher expectations of symptoms.
Conclusions: In order to reduce nocebo induced symptoms associated with medication or
other interventions clinicians could: reduce expectations of symptoms, limit suggestions of
symptoms, correct unrealistic dose perceptions, and reduce exposure to people experiencing
side effects. There is some evidence that we should do this especially for persons with at-risk
personality types, though exactly which personality types these are requires further research.
These suggestions have a downside in terms of consent and paternalism, but there is scope to
develop innovative ways to reduce nocebo effects without withholding information.
Key words: nocebo effect, predictors, symptoms, inert exposure, review
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Adverse drug reactions (ADRs) are common (Davies et al., 2009), and can have
serious implications in terms of patient well-being and adherence (Ammassari et al., 2001) as
well as significant financial costs for health services (Monguio, Otero, & Rovira, 2003;
NICE, 2009). However, ADRs are not always related to the physiological action of the
medication (Faasse & Petrie, 2013). Only 10.9% of reported ADRs to commonly prescribed
drugs are clearly attributable to the medication (de Frutos Hernansanz et al., 1994). It is
thought a nocebo effect may play a role in the formation of other apparent side effects
(Barsky, Saintfort, Rogers, & Borus, 2002). As well as medication side effects, nocebo
effects have been implicated in symptoms attributed to technological exposures such as
electro-magnetic fields (EMF) from mobile phones and Wi-Fi (Baliatsas et al., 2012; Rubin,
Cleare, & Wessely, 2008). A nocebo effect is the experience of negative symptoms following
exposure to an inert substance, which are triggered or exacerbated by psychological
mechanisms such as expectations (Kennedy, 1961). The name ‘nocebo’ was created to
distinguish between the desirable (‘placebo’) and undesirable effects of an inert exposure
(Hauser, Hansen, & Enck, 2012), although in practice the distinction between undesirable and
desirable is not always clear cut. For example increased alertness maybe beneficial in some
contexts (e.g. prior to an examination) and detrimental in others (e.g. prior to sleep).
Current literature suggests there are three main mechanisms for a nocebo effect;
misattribution, expectation, and learning. Misattribution theory suggests that people
misattribute pre-existing symptoms to the effects of a new exposure (although some authors
believe that misattribution does not technically constitute a nocebo effect, see Enck, Bingel,
Schedlowski & Rief, 2013; Colloca & Miller, 2011). Symptoms are common in everyday life
(Petrie, Faasse, Critchon, & Grey, 2014), and although often harmless and short-lived, when
people are subjected to a new exposure, symptoms that were present before or occur
coincidentally are available to be mistakenly attributed to it (Petrie et al., 2005; Petrie, Moss-
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Morris, Grey, & Shaw, 2004). Therefore factors such as high baseline symptoms or high self-
awareness may serve as risk factors for nocebo effects resulting from this mechanism.
Negative expectations can also mediate nocebo effects (Hahn, 1997), and may in turn arise
through explicit suggestions about the effects of an exposure (Jaen & Dalton, 2014; Myers,
Cairns, & Singer, 1987), or predisposing factors such as pessimism (Geers, Helfer, Kosbab,
Weiland, & Landry, 2005). These negative expectations can make the individual more likely
to attend to new or current sensations, and attribute them to the exposure (Barsky et al.,
2002). The response expectancy theory suggests that it is also possible for negative
expectations to act more directly, with an expectation of, for example anxiety, being itself
provoke anxiety thereby directly causing the negative effect that was expected (Kirsch,
1997a,b). The last mechanism, learning, can elicit nocebo effects through association or
social observation. For example, if an inert stimulus has been previously paired with a
symptom-inducing stimulus (Barsky et al., 2002), which may occur through conscious or
non-conscious mechanisms (Stewart-Williams, 2004), or through observing someone else
experience symptoms to the same exposure (Vogtle, Barke, & Kroner-Herwig, 2013).
Given the significant costs nocebo effects can have on patient quality of life and
health services it is important to develop interventions to minimise these effects from
occurring. Many risk factors have been implicated, but no study has systematically reviewed
these to identify those which are the strongest predictors of nocebo effects; something that
would assist in the development of such interventions. Instead, previous systematic reviews
have focused on the magnitude of nocebo effects for a specific symptom, e.g. Petersen et al.
(2014) or in clinical trials of experimental medical treatments (Hauser, Bartram, Bartram-
Wunn, & Tolle, 2012). One review (Symon, Williams, Adelasoye, & Cheyne, 2015) has
provided a preliminary assessment of some of the risk factors involved in nocebo effects.
However this “scoping review” identified only 17 papers – a limited subset of the available