Nocebos in rheumatology: emerging concepts and their implications for clinical practice


Nocebo effects are noxious reactions to therapeutic interventions that occur because of negative expectations of the patient. In the past decade, neurobiological data have revealed specific neural pathways induced by nocebos (that is, interventions that cause nocebo effects), as well as the associated mechanisms and predisposing factors of nocebo effects. Epidemiological data suggest that nocebos can have a notable effect on medication adherence, clinical outcomes and health-care policy. Meta-analyses of randomized controlled trials (RCTs) of patients with rheumatic and musculoskeletal diseases (RMDs) indicate that withdrawal of treatment by placebo-arm participants owing to adverse events is common; a proportion of these events could be nocebo effects. Moreover, in large-scale, open-label studies of patients with RMDs who transition from bio-originator to biosimilar therapeutics, biosimilar retention rates were much lower than in previous double-blind switch RCTs. This discrepancy suggests that in addition to the lack of response in some patients because of intrinsic differences between the drugs, nocebos might have an important role in low biosimilar retention, thus increasing the need for awareness and early identification of nocebo effects by rheumatologists and allied health-care professionals.

Key points

  • Nocebo effects are noxious changes in a patient’s symptoms or physiological condition that occur because of the patient’s negative anticipation of treatment, and might result in suboptimal outcomes and non-adherence.

  • Nocebo effects are observed in patients with rheumatic and musculoskeletal diseases, and might hinder the transition of patients to biosimilars.

  • Physicians should be aware of the risk factors for nocebo effects, which can be categorized as features relating to the patient, physician, disease, health-care setting or drug.

  • Physicians should make efforts to measure, prevent and address nocebo effects in clinical practice and interventional trials.

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Fig. 1: Neural pathways involved in nocebo-related pain modulation.
Fig. 2: Factors promoting nocebo effects in clinical practice.


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Reviewer information

Nature Reviews Rheumatology thanks J. Kay, R. Fleischmann, S. Palerma and U. Bingel for their contribution to the peer review of this work.

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The authors contributed equally to all aspects of the article.

Correspondence to Petros P. Sfikakis.

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E.K. declares no competing interests. D.D.M has received honoraria and/or research and travel grants and/or consultation fees from Allegra, Amgen, Biogen, Cephaly, Electrocore, Elli Lilly, Merck-Serono, Merz, Novartis, Roche, Sanofi and Teva. G.D.K has received honoraria for lectures and advisory boards and/or support for the organization of educational meetings and/or attendance to congresses from Abbvie, Aenorasis, BMS, Genesis, GSK, MSD, Novartis, Roche, Pfizer and UCB. P.P.S. has received honoraria for lectures and/or advisory boards and/or funding for research and congress attendances from Abbvie, Aenorasis, Amgen, BMS, Boehringer, Elli Lilly, Elpen, Genesis, Jannsen, Pfizer, MSD, Novartis, Roche, Sanofi and UCB.

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The word nocebo is derived from the Latin word noceo (‘to harm’) and is the opposite of placebo; nocebo denotes a medical intervention that causes adverse events owing to negative expectations of the patient, and can include inert substances or medications, medical procedures or patient–physician encounters.

Nocebo effects

Noxious changes in a patient’s symptoms or physiologic condition caused by a nocebo; nocebo effects can result in suboptimal outcomes and non-adherence.


The word placebo is derived from the latin term placeo (“I shall please”) and denotes a medical intervention that induces beneficial effects owing to positive expectations of the patient.

Nocebo response

A neurobiological alteration of the brain–body unit that is not directly attributable to a drug’s pharmacokinetics and might cause a negative treatment outcome.

Placebo effect

An improvement in a patient’s symptoms or physiologic condition resulting from a placebo.

Placebo response

A positive treatment outcome caused by a placebo manipulation; the placebo response reflects the neurobiological and psychophysiological response of an individual to an inert substance or sham treatment and is mediated by various factors within the treatment context.


An increased sensitivity to pain from a stimulus that normally provokes pain.

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Kravvariti, E., Kitas, G.D., Mitsikostas, D.D. et al. Nocebos in rheumatology: emerging concepts and their implications for clinical practice. Nat Rev Rheumatol 14, 727–740 (2018).

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