How the number of learning trials affects placebo and nocebo responses
Open accessAbstract
Conditioning procedures are used in many placebo studies because evidence suggests that conditioning-related placebo responses are usually more robust than those induced by verbal suggestions alone. However, it has not been shown whether there is a causal relation between the number of conditioning trials and the resistance to extinction of placebo and nocebo responses. Here we test the effects of either one or four sessions of conditioning on the modulation of both non-painful and painful stimuli delivered to the dorsum of the foot. Placebo and nocebo manipulations were obtained by pairing green or red light to a series of stimuli that were made lower or higher with respect to a yellow light associated with a series of control stimuli. Subjects were told that the lights would indicate a treatment that would reduce or increase non-painful and painful stimuli to the foot. They were randomly assigned to either Group 1 or 2. Group 1 underwent one session of conditioning and Group 2 received four sessions of conditioning. We found that one session of conditioning (Group 1) induced nocebo responses, but not placebo responses in no pain condition. After one session of conditioning, we observed both nocebo and placebo responses to painful stimulation. However, these effects extinguished over time. Conversely, four sessions of conditioning (Group 2) induced robust placebo and nocebo responses to both non-painful and painful stimuli that persisted over the entire experiment. These findings suggest that the strength of learning may be clinically important for producing long-lasting placebo effects.
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Behavioral measures alone have been used in most direct comparisons of placebo and nocebo effects.
“Most of these studies have involved behavioral measures only (Benedetti et al., 2014; Benedetti et al., 2003; Colloca et al., 2010; Colloca et al., 2008).”
From Distinct neural representations of placebo and nocebo effects (2015) · cites this paper as Colloca et al., 2010
Direct comparisons of placebo and nocebo effects are rare.
“To date, only a few studies have directly compared placebo and nocebo effects.”
From Distinct neural representations of placebo and nocebo effects (2015) · cites this paper as Colloca et al., 2010
Factors such as conditioning, psychosocial context, facilitator attention, setting, posture, and demand characteristics might mediate health gains attributed to mindfulness meditation.
“Nonspecific and potentially confounding variables, such as conditioning effects, psychosocial contexts, facilitator attention, intervention setting, body posture, and/or demand characteristics associated with the belief that one is practicing meditation,15, 27, 135 could mediate mindfulness meditation–related health improvements.136, 137”
From Mindfulness meditation-based pain relief: a mechanistic account (2016) · cites this paper as [136]
Negative expectations induced by medical staff lead to the formation of nocebo effects.
“Indeed, negative expectations that are induced by the medical staff also lead to the formation of nocebo effects.15,31”
From Nocebo and pain: an overview of the psychoneurobiological mechanisms (2017) · cites this paper as [31]
These findings fit with the notion that optimism and anxiety modulate nocebo, as well as placebo, responses.
“These findings well fit with the notion that optimism and anxiety modulate nocebo, as well as placebo, responses12252641.”
From Changes in perception of treatment efficacy are associated to the magnitude of the nocebo effect and to personality traits (2016) · cites this paper as [12]
In a previous study in the context of pain, a correlation was found between nocebo responses and both anxiety scales (state and trait).
“Moreover, in a previous study in the context of pain, a correlation was found between nocebo responses and both anxiety scales (state and trait)12, supporting the link between anxiety and the nocebo effect.”
From Changes in perception of treatment efficacy are associated to the magnitude of the nocebo effect and to personality traits (2016) · cites this paper as [12]
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- Authors
- Colloca, L., Petrovic, P., Wager, T. D., Ingvar, M., & Benedetti, F.
- Affiliations
- National Institutes of Health (US)
- University of Colorado Boulder (US)
- Karolinska Institutet (SE)
- University of Turin (IT)
- Corresponding author
- Colloca, Luana
- Venue
- Pain
- Published
- 2010-11
- Volume
- 151
- Issue
- 2
- Pages
- 430-439
- ISSN
- 0304-3959 (ISSN-L)
- PMC
- PMC2955814
- OpenAlex
- W2163724593
- Cited by
- 300
- References
- 50
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 17 · 2023: 26 · 2022: 21 · 2021: 15 · 2020: 17 · 2019: 21 · 2018: 30 · 2017: 23 · 2016: 15 · 2015: 19 · 2014: 22 · 2013: 17 · 2012: 12
- FWCI
- 8.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Pain (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- International Association for the Study of Pain
- National Institutes of Health (Z99 AT999999)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- placebo response, nocebo effect, classical conditioning, extinction, pain perception, foot dorsum, verbal suggestion
- MeSH terms
- Adult, Analysis of Variance, Conditioning, Psychological, Electric Stimulation, Female, Humans, Male, Pain, Pain Measurement, Photic Stimulation, Placebos, Psychological Tests, Psychophysics, Statistics as Topic, Time Factors, Placebo Effect, Pain Threshold, Young Adult
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