Nocebo hyperalgesia: how anxiety is turned into pain
Abstract
PURPOSE OF REVIEW: Nocebo hyperalgesia is a phenomenon that is opposite to placebo analgesia and whereby expectation of pain increase plays a crucial role. In recent times, both the neuroanatomical and the neurochemical bases of the nocebo effect and of nocebo-related effects have begun to be explored. Here, we highlight recent advances in our understanding of the neurobiology of the nocebo hyperalgesic effect. RECENT FINDINGS: A typical nocebo hyperalgesic response occurs following the administration of an inert substance which the subject believes to be a hyperalgesic agent (negative placebo or nocebo). It has been shown that the subject's negative expectations of pain worsening induce anticipatory anxiety about the impending pain increase and this triggers the activation of cholecystokinin that, in turn, facilitates pain transmission. Accordingly, cholecystokinin antagonists have been found to prevent this anxiety-induced hyperalgesia. Brain-imaging studies have shown that the perceived intensity of a painful stimulus following negative expectations of pain increase is higher than in the absence of negative expectations and this is associated with changes in activation of specific brain regions. SUMMARY: Since pain appears to be amplified by anxiety through the activation of cholecystokininergic systems, new therapeutic strategies, such as new cholecystokinin antagonists, can be envisaged whenever pain has an important anxiety component.
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Nocebo hyperalgesia has received less research attention than placebo analgesia.
“Relatively fewer studies have focused on nocebo hyperalgesia (Benedetti et al., 2003; Colloca and Benedetti, 2007; Colloca and Finniss, 2012; Geuter and Buchel, 2013; Kong et al., 2008; Schmid et al., 2013; Scott et al., 2008).”
From Distinct neural representations of placebo and nocebo effects (2015) · cites this paper as Colloca and Benedetti, 2007
Learning appears to influence both the occurrence of nocebo and placebo effects; however, the repetition of associations is less important in promoting nocebo hyperalgesia than in consolidating placebo analgesia.
“For example, learning appears to influence both the occurrence of nocebo and placebo effects; however, the repetition of associations is less important in promoting nocebo hyperalgesia than in consolidating placebo analgesia.24”
From Nocebo and pain: an overview of the psychoneurobiological mechanisms (2017) · cites this paper as [24]
The duration of prior events marked with exposure to pain is relevant for the development and perpetuation of nocebo-induced algesia.
“The duration of prior events marked with exposure to pain is also relevant for the development and perpetuation of nocebo-induced algesia.24,26,33–35”
From Nocebo and pain: an overview of the psychoneurobiological mechanisms (2017) · cites this paper as [24]
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Self-citation
- Authors
- Colloca, L., & Benedetti, F.
- Affiliations
- University of Turin (IT)
- Corresponding author
- Benedetti, Fabrizio
- Venue
- Current Opinion in Anaesthesiology
- Published
- 2007-10
- Volume
- 20
- Issue
- 5
- Pages
- 435-439
- ISSN
- 0952-7907 (ISSN-L)
- OpenAlex
- W2028713040
- Cited by
- 350
- References
- 51
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 18 · 2023: 12 · 2022: 28 · 2021: 17 · 2020: 65 · 2019: 27 · 2018: 12 · 2017: 15 · 2016: 18 · 2015: 16 · 2014: 21 · 2013: 22 · 2012: 14
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Opinion in Anaesthesiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Regione Piemonte
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
- Keywords
- nocebo hyperalgesia, anxiety, pain anticipation, cholecystokinin, cholecystokinin antagonists, placebo analgesia, anticipatory anxiety, pain perception, brain activation, neurobiology of pain
- MeSH terms
- Animals, Anxiety, Cholecystokinin, Humans, Hyperalgesia, Placebo Effect, Rats
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