How the number of learning trials affects placebo and nocebo responses
Luana Colloca, Predrag Petrovic, Tor D Wager, Martin Ingvar, Fabrizio Benedetti, Luana Colloca, Predrag Petrovic, Tor D Wager, Martin Ingvar, Fabrizio Benedetti
Abstract
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.
Conflict of interest statement
The authors have no conflicts of interest to declare.
Published by Elsevier B.V.
Figures
![Figure 1. Experimental design](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2955814/bin/nihms230194f1.jpg)
![Figure 2. Results following a short-lasting module…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2955814/bin/nihms230194f2.jpg)
Figure 3. Results following a long-lasting module…
Figure 3. Results following a long-lasting module of learning (Group 2)
The histograms present the…
Figure 4. Placebo and nocebo correlations
After…
Figure 4. Placebo and nocebo correlations
After a short-training in Group 1, placebo and nocebo…
Figure 5. Average of the responses in…
Figure 5. Average of the responses in each group and condition
It can be noted…
- Placebo analgesia induced by social observational learning.Colloca L, Benedetti F. Colloca L, et al. Pain. 2009 Jul;144(1-2):28-34. doi: 10.1016/j.pain.2009.01.033. Epub 2009 Mar 10. Pain. 2009. PMID: 19278785 Clinical Trial.
- Induction of nocebo and placebo effects on itch and pain by verbal suggestions.van Laarhoven AIM, Vogelaar ML, Wilder-Smith OH, van Riel PLCM, van de Kerkhof PCM, Kraaimaat FW, Evers AWM. van Laarhoven AIM, et al. Pain. 2011 Jul;152(7):1486-1494. doi: 10.1016/j.pain.2011.01.043. Epub 2011 Feb 24. Pain. 2011. PMID: 21353388 Clinical Trial.
- Neuromodulation of conditioned placebo/nocebo in heat pain: anodal vs cathodal transcranial direct current stimulation to the right dorsolateral prefrontal cortex.Egorova N, Yu R, Kaur N, Vangel M, Gollub RL, Dougherty DD, Kong J, Camprodon JA. Egorova N, et al. Pain. 2015 Jul;156(7):1342-1347. doi: 10.1097/j.pain.0000000000000163. Pain. 2015. PMID: 25806605 Free PMC article.
- Nocebo and lessebo effects.A Mestre T. A Mestre T. Int Rev Neurobiol. 2020;153:121-146. doi: 10.1016/bs.irn.2020.04.005. Epub 2020 Jun 9. Int Rev Neurobiol. 2020. PMID: 32563285 Review.
- Placebo and nocebo effects in itch and pain.Evers AW, Bartels DJ, van Laarhoven AI. Evers AW, et al. Handb Exp Pharmacol. 2014;225:205-14. doi: 10.1007/978-3-662-44519-8_12. Handb Exp Pharmacol. 2014. PMID: 25304534 Review.
- Harnessing the placebo effect to enhance emotion regulation effectiveness and choice.Shafir R, Israel M, Colloca L. Shafir R, et al. Sci Rep. 2023 Feb 9;13(1):2373. doi: 10.1038/s41598-023-29045-6. Sci Rep. 2023. PMID: 36759537 Free PMC article. Clinical Trial.
- Pain, from perception to action: A computational perspective.Chen ZS, Wang J. Chen ZS, et al. iScience. 2022 Dec 1;26(1):105707. doi: 10.1016/j.isci.2022.105707. eCollection 2023 Jan 20. iScience. 2022. PMID: 36570771 Free PMC article. Review.
- Placebo and nocebo effects: from observation to harnessing and clinical application.Tu Y, Zhang L, Kong J. Tu Y, et al. Transl Psychiatry. 2022 Dec 24;12(1):524. doi: 10.1038/s41398-022-02293-2. Transl Psychiatry. 2022. PMID: 36564374 Free PMC article. Review.
- Vaccine hesitancy prospectively predicts nocebo side-effects following COVID-19 vaccination.Hoffman YSG, Levin Y, Palgi Y, Goodwin R, Ben-Ezra M, Greenblatt-Kimron L. Hoffman YSG, et al. Sci Rep. 2022 Dec 5;12(1):20018. doi: 10.1038/s41598-022-21434-7. Sci Rep. 2022. PMID: 36470896 Free PMC article.
- Differences between experimental and placebo arms in manual therapy trials: a methodological review.D'Alessandro G, Ruffini N, Aquino A, Galli M, Innocenti M, Tramontano M, Cerritelli F. D'Alessandro G, et al. BMC Med Res Methodol. 2022 Aug 8;22(1):219. doi: 10.1186/s12874-022-01704-8. BMC Med Res Methodol. 2022. PMID: 35941533 Free PMC article. Review.
- Clinical Trial
- Research Support, Non-U.S. Gov't
- Adult
- Analysis of Variance
- Conditioning, Psychological / physiology*
- Electric Stimulation / adverse effects
- Female
- Humans
- Male
- Pain / drug therapy*
- Pain / etiology
- Pain / psychology*
- Pain Measurement / methods
- Pain Threshold / drug effects
- Pain Threshold / physiology
- Photic Stimulation / methods
- Placebo Effect*
- Placebos / therapeutic use*
- Psychological Tests
- Psychophysics / methods
- Statistics as Topic
- Time Factors
- Young Adult
- Placebos
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![Figure 3. Results following a long-lasting module…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2955814/bin/nihms230194f3.jpg)
Figure 4. Placebo and nocebo correlations
After…
Figure 4. Placebo and nocebo correlations
After a short-training in Group 1, placebo and nocebo…
Figure 5. Average of the responses in…
Figure 5. Average of the responses in each group and condition
It can be noted…
- Placebo analgesia induced by social observational learning.Colloca L, Benedetti F. Colloca L, et al. Pain. 2009 Jul;144(1-2):28-34. doi: 10.1016/j.pain.2009.01.033. Epub 2009 Mar 10. Pain. 2009. PMID: 19278785 Clinical Trial.
- Induction of nocebo and placebo effects on itch and pain by verbal suggestions.van Laarhoven AIM, Vogelaar ML, Wilder-Smith OH, van Riel PLCM, van de Kerkhof PCM, Kraaimaat FW, Evers AWM. van Laarhoven AIM, et al. Pain. 2011 Jul;152(7):1486-1494. doi: 10.1016/j.pain.2011.01.043. Epub 2011 Feb 24. Pain. 2011. PMID: 21353388 Clinical Trial.
- Neuromodulation of conditioned placebo/nocebo in heat pain: anodal vs cathodal transcranial direct current stimulation to the right dorsolateral prefrontal cortex.Egorova N, Yu R, Kaur N, Vangel M, Gollub RL, Dougherty DD, Kong J, Camprodon JA. Egorova N, et al. Pain. 2015 Jul;156(7):1342-1347. doi: 10.1097/j.pain.0000000000000163. Pain. 2015. PMID: 25806605 Free PMC article.
- Nocebo and lessebo effects.A Mestre T. A Mestre T. Int Rev Neurobiol. 2020;153:121-146. doi: 10.1016/bs.irn.2020.04.005. Epub 2020 Jun 9. Int Rev Neurobiol. 2020. PMID: 32563285 Review.
- Placebo and nocebo effects in itch and pain.Evers AW, Bartels DJ, van Laarhoven AI. Evers AW, et al. Handb Exp Pharmacol. 2014;225:205-14. doi: 10.1007/978-3-662-44519-8_12. Handb Exp Pharmacol. 2014. PMID: 25304534 Review.
- Harnessing the placebo effect to enhance emotion regulation effectiveness and choice.Shafir R, Israel M, Colloca L. Shafir R, et al. Sci Rep. 2023 Feb 9;13(1):2373. doi: 10.1038/s41598-023-29045-6. Sci Rep. 2023. PMID: 36759537 Free PMC article. Clinical Trial.
- Pain, from perception to action: A computational perspective.Chen ZS, Wang J. Chen ZS, et al. iScience. 2022 Dec 1;26(1):105707. doi: 10.1016/j.isci.2022.105707. eCollection 2023 Jan 20. iScience. 2022. PMID: 36570771 Free PMC article. Review.
- Placebo and nocebo effects: from observation to harnessing and clinical application.Tu Y, Zhang L, Kong J. Tu Y, et al. Transl Psychiatry. 2022 Dec 24;12(1):524. doi: 10.1038/s41398-022-02293-2. Transl Psychiatry. 2022. PMID: 36564374 Free PMC article. Review.
- Vaccine hesitancy prospectively predicts nocebo side-effects following COVID-19 vaccination.Hoffman YSG, Levin Y, Palgi Y, Goodwin R, Ben-Ezra M, Greenblatt-Kimron L. Hoffman YSG, et al. Sci Rep. 2022 Dec 5;12(1):20018. doi: 10.1038/s41598-022-21434-7. Sci Rep. 2022. PMID: 36470896 Free PMC article.
- Differences between experimental and placebo arms in manual therapy trials: a methodological review.D'Alessandro G, Ruffini N, Aquino A, Galli M, Innocenti M, Tramontano M, Cerritelli F. D'Alessandro G, et al. BMC Med Res Methodol. 2022 Aug 8;22(1):219. doi: 10.1186/s12874-022-01704-8. BMC Med Res Methodol. 2022. PMID: 35941533 Free PMC article. Review.
- Clinical Trial
- Research Support, Non-U.S. Gov't
- Adult
- Analysis of Variance
- Conditioning, Psychological / physiology*
- Electric Stimulation / adverse effects
- Female
- Humans
- Male
- Pain / drug therapy*
- Pain / etiology
- Pain / psychology*
- Pain Measurement / methods
- Pain Threshold / drug effects
- Pain Threshold / physiology
- Photic Stimulation / methods
- Placebo Effect*
- Placebos / therapeutic use*
- Psychological Tests
- Psychophysics / methods
- Statistics as Topic
- Time Factors
- Young Adult
- Placebos
![Figure 4. Placebo and nocebo correlations](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2955814/bin/nihms230194f4.jpg)
Figure 5. Average of the responses in…
Figure 5. Average of the responses in each group and condition
It can be noted…
![Figure 5. Average of the responses in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2955814/bin/nihms230194f5.jpg)
Source: PubMed