Nonconscious activation of placebo and nocebo pain responses
Open accessAbstract
The dominant theories of human placebo effects rely on a notion that consciously perceptible cues, such as verbal information or distinct stimuli in classical conditioning, provide signals that activate placebo effects. However, growing evidence suggest that behavior can be triggered by stimuli presented outside of conscious awareness. Here, we performed two experiments in which the responses to thermal pain stimuli were assessed. The first experiment assessed whether a conditioning paradigm, using clearly visible cues for high and low pain, could induce placebo and nocebo responses. The second experiment, in a separate group of subjects, assessed whether conditioned placebo and nocebo responses could be triggered in response to nonconscious (masked) exposures to the same cues. A total of 40 healthy volunteers (24 female, mean age 23 y) were investigated in a laboratory setting. Participants rated each pain stimulus on a numeric response scale, ranging from 0 = no pain to 100 = worst imaginable pain. Significant placebo and nocebo effects were found in both experiment 1 (using clearly visible stimuli) and experiment 2 (using nonconscious stimuli), indicating that the mechanisms responsible for placebo and nocebo effects can operate without conscious awareness of the triggering cues. This is a unique experimental verification of the influence of nonconscious conditioned stimuli on placebo/nocebo effects and the results challenge the exclusive role of awareness and conscious cognitions in placebo responses.
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For Dataset 1, a sample size of 30 subjects was determined by examining previous studies investigating the effect of expectation on electrical pain and more subtle effects such as the effect of certainty or subliminally presented cue on pain intensity rating, which typically recruit 15-30 participants.
“For Dataset 1 we determined an appropriate sample size of 30 subjects by examining previous studies investigating the effect of expectation on electrical pain and more subtle effects such as the effect of certainty or subliminally presented cue on pain intensity rating, which typically recruit 15–30 participants (Brown, Seymour, El-Deredy, & Jones, 2008; Colloca & Benedetti, 2006; Jensen, Kaptchuk”
From Boundary effects of expectation in human pain perception (2019) · cites this paper as Jensen, Kaptchuk, Kirsch, Raicek, Lindstrom, Berna, Gollub, Ingvar, & Kong, 2012
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Cites
Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome
Kaptchuk, T. J., Kelley, J. M., Conboy, L. A., Davis, R. B., Kerr, C. E., Jacobson, E. E., Kirsch, I., Schyner, R. N., Nam, B. H., Nguyen, L. T., et al. (2008) · BMJ · doi:10.1136/bmj.39524.439618.25 · Cited by 1,196 · see citing works
Self-citationBenedetti, F., Pollo, A., Lopiano, L., Lanotte, M., Vighetti, S., & Rainero, I. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-10-04315.2003 · Cited by 788 · see citing works
Behavioral Priming: It’s all in the Mind, but whose Mind?
Doyen, S., Klein, O., Pichon, C.-L., & Cleeremans, A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029081 · Cited by 670 · see citing works
Petrovic, P., Dietrich, T., Fransson, P., Andersson, J., Carlsson, K., & Ingvar, M. (2005) · Neuron · doi:10.1016/j.neuron.2005.05.023 · Cited by 437 · see citing works
Self-citationKong, J., Gollub, R. L., Rosman, I. S., Webb, J. M., Vangel, M. G., Kirsch, I., & Kaptchuk, T. J. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.3556-05.2006 · Cited by 395 · see citing works
Self-citationThe role of conditioning and verbal expectancy in the placebo response
Voudouris, N. J., Peck, C. L., & Coleman, G. (1990) · Pain · doi:10.1016/0304-3959(90)90057-k · Cited by 369 · see citing works
Subliminal Instrumental Conditioning Demonstrated in the Human Brain
Pessiglione, M., Petrovic, P., Daunizeau, J., Palminteri, S., Dolan, R. J., & Frith, C. D. (2008) · Neuron · doi:10.1016/j.neuron.2008.07.005 · Cited by 308 · see citing works
ESTEVES, F., PARRA, C., DIMBERG, U., & ÖHMAN, A. (1994) · Psychophysiology · doi:10.1111/j.1469-8986.1994.tb02446.x · Cited by 301 · see citing works
A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect
Kong, J., Gollub, R. L., Polich, G., Kirsch, I., LaViolette, P., Vangel, M., Rosen, B., & Kaptchuk, T. J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.2944-08.2008 · Cited by 263 · see citing works
Self-citationClassical conditioning, awareness, and brain systems
Clark, R. E., Manns, J. R., & Squire, L. R. (2002) · Trends in Cognitive Sciences · doi:10.1016/s1364-6613(02)02041-7 · Cited by 249 · see citing works
The role of cognition in classical and operant conditioning
Kirsch, I., Lynn, S. J., Vigorito, M., & Miller, R. R. (2004) · Journal of Clinical Psychology · doi:10.1002/jclp.10251 · Cited by 192 · see citing works
Self-citationPlacebo analgesia is not due to compliance or habituation: EEG and behavioural evidence
Watson, A., El-Deredy, W., Vogt, B. A., & Jones, A. K. P. (2007) · NeuroReport · doi:10.1097/wnr.0b013e3280c1e2a8 · Cited by 79 · see citing works
Flagged first, then by citations
Research works printed but not linked: 4
- Dijksterhuis A, Aarts H, Smith PK (2005) The power of the subliminal: On subliminal persuasion and other potential applications. The New Unconscious: Social Cognition and Social Neuroscience (Oxford Univ Press, New York).
- Phelps E (2005) The interaction of emotion and cognition: The relation between the human amygdala and cognitive awareness. The New Unconscious: Social Cognition and Social Neuroscience, eds Hassin RR, Uleman JS, Bargh JA (Oxford Univ Press, New York).
- Benedetti F (2009) Placebo Effects: Understanding the Mechanisms in Health and Disease (Oxford Univ Press, New York).
- Gracely R, Dubner R, Deeter W, Wolskee P (1985) Clinicians' expectations influence placebo analgesia. Lancet 1(8419):43.
Cited by
Sorted by citations
Placebo Analgesia: A Predictive Coding Perspective
Büchel, C., Geuter, S., Sprenger, C., & Eippert, F. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.042 · Cited by 505 · see citing works
Placebo and the New Physiology of the Doctor-Patient Relationship
Benedetti, F. (2013) · Physiological Reviews · doi:10.1152/physrev.00043.2012 · Cited by 492 · see citing works
Altered Placebo and Drug Labeling Changes the Outcome of Episodic Migraine Attacks
Kam-Hansen, S., Jakubowski, M., Kelley, J. M., Kirsch, I., Hoaglin, D. C., Kaptchuk, T. J., & Burstein, R. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3006175 · Cited by 399 · see citing works
Self-citationPlacebo analgesia: Psychological and neurobiological mechanisms
Colloca, L., Klinger, R., Flor, H., & Bingel, U. (2013) · Pain · doi:10.1016/j.pain.2013.02.002 · Cited by 263 · see citing works
Psychological Interventions for the Treatment of Chronic Pain in Adults
Driscoll, M. A., Edwards, R. R., Becker, W. C., Kaptchuk, T. J., & Kerns, R. D. (2021) · Psychological Science in the Public Interest · doi:10.1177/15291006211008157 · Cited by 176 · see citing works
Self-citationNocebo and pain: an overview of the psychoneurobiological mechanisms
Blasini, M., Corsi, N., Klinger, R., & Colloca, L. (2017) · PAIN Reports · doi:10.1097/pr9.0000000000000585 · Cited by 139 · see citing works
“Experimental evidence suggests that negative expectations elicited by verbal suggestions are generally powerful enough to produce nocebo effects of higher effect size when compared to the placebo effect, for which it is critical to have a first-hand experience where a positive outcome is learned and consolidated.(34,5…”
BackgroundClassical conditioning of analgesic and hyperalgesic pain responses without conscious awareness
Jensen, K., Kirsch, I., Odmalm, S., Kaptchuk, T. J., & Ingvar, M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1504567112 · Cited by 130 · see citing works
Self-citationConditioned Placebo Analgesia Persists When Subjects Know They Are Receiving a Placebo
Schafer, S. M., Colloca, L., & Wager, T. D. (2015) · The Journal of Pain · doi:10.1016/j.jpain.2014.12.008 · Cited by 117 · see citing works
Placebo 2.0: the impact of expectations on analgesic treatment outcome
Bingel, U. (2020) · Pain · doi:10.1097/j.pain.0000000000001981 · Cited by 113 · see citing works
Boundary effects of expectation in human pain perception
Hird, E. J., Charalambous, C., El-Deredy, W., Jones, A. K. P., & Talmi, D. (2019) · Scientific Reports · doi:10.1038/s41598-019-45811-x · Cited by 68 · see citing works
Egorova, N., Yu, R., Kaur, N., Vangel, M., Gollub, R. L., Dougherty, D. D., Kong, J., & Camprodon, J. A. (2015) · Pain · doi:10.1097/j.pain.0000000000000163 · Cited by 63 · see citing works
Self-citationHypnotic susceptibility modulates brain activity related to experimental placebo analgesia
Huber, A., Lui, F., & Porro, C. A. (2013) · Pain · doi:10.1016/j.pain.2013.03.031 · Cited by 53 · see citing works
Placebo Responses in Genetically Determined Intellectual Disability: A Meta-Analysis
Curie, A., Yang, K., Kirsch, I., Gollub, R. L., des Portes, V., Kaptchuk, T. J., & Jensen, K. B. (2015) · PLOS ONE · doi:10.1371/journal.pone.0133316 · Cited by 43 · see citing works
Self-citationSubliminal (latent) processing of pain and its evolution to conscious awareness
Borsook, D., Youssef, A. M., Barakat, N., Sieberg, C. B., & Elman, I. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.02.015 · Cited by 21 · see citing works
Certainty of genuine treatment increases drug responses among intellectually disabled patients
Jensen, K. B., Kirsch, I., Pontén, M., Rosén, A., Yang, K., Gollub, R. L., des Portes, V., Kaptchuk, T. J., & Curie, A. (2017) · Neurology · doi:10.1212/wnl.0000000000003934 · Cited by 17 · see citing works
Self-citation
- Authors
- Jensen, K. B., Kaptchuk, T. J., Kirsch, I., Raicek, J., Lindstrom, K. M., Berna, C., Gollub, R. L., Ingvar, M., & Kong, J.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Department of Clinical Neuroscience, Osher Center for Integrative Medicine, Karolinska Institutet, 17176 Stockholm, Sweden; and
- Karolinska Institutet (SE)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-09-10
- Volume
- 109
- Issue
- 39
- Pages
- 15959-15964
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3465419
- OpenAlex
- W1990284269
- Cited by
- 305
- References
- 12
- Citations by year
- 2026: 4 · 2025: 15 · 2024: 23 · 2023: 15 · 2022: 13 · 2021: 27 · 2020: 29 · 2019: 30 · 2018: 26 · 2017: 25 · 2016: 25 · 2015: 26 · 2014: 25 · 2013: 18 · 2012: 3
- FWCI
- 11.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Center for Complementary and Integrative Health (R01AT006364, R03AT218317, K24AT004095, R01AT005280, R21AT004497)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Dentistry › Oral Surgery › Dental Anxiety and Anesthesia Techniques
- Keywords
- placebo effect, nocebo effect, unconscious processes, masked stimuli, thermal pain, classical conditioning, conscious awareness, pain perception
- MeSH terms
- Adult, Female, Humans, Male, Pain, Placebo Effect, Pain Perception
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