Different Placebos, Different Mechanisms, Different Outcomes: Lessons for Clinical Trials
Fabrizio Benedetti, Sara Dogue, Fabrizio Benedetti, Sara Dogue
Abstract
Clinical trials use placebos with the assumption that they are inert, thus all placebos are considered to be equal. Here we show that this assumption is wrong and that different placebo procedures are associated to different therapeutic rituals which, in turn, trigger different mechanisms and produce different therapeutic outcomes. We studied high altitude, or hypobaric hypoxia, headache, in which two different placebos were administered. The first was placebo oxygen inhaled through a mask, whereas the second was placebo aspirin swallowed with a pill. Both placebos were given after a conditioning procedure, whereby either real oxygen or real aspirin was administered for three consecutive sessions to reduce headache pain. We found that after real oxygen conditioning, placebo oxygen induced pain relief along with a reduction in ventilation, blood alkalosis and salivary prostaglandin (PG)E2, yet without any increase in blood oxygen saturation (SO2). By contrast, after real aspirin conditioning, placebo aspirin induced pain relief through the inhibition of all the products of cyclooxygenase, that is, PGD2, PGE2, PGF2, PGI2, thromboxane (TX)A2, without affecting ventilation and blood alkalosis. Therefore, two different placebos, associated to two different therapeutic rituals, used two different pathways to reduce headache pain. The analgesic effect following placebo oxygen was superior to placebo aspirin. These findings show that different placebos may use different mechanisms to reduce high altitude headache, depending on the therapeutic ritual and the route of administration. In clinical trials, placebos and outcome measures should be selected very carefully in order not to incur in wrong interpretations.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
![Fig 1. Rationale of the study.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4633056/bin/pone.0140967.g001.jpg)
![Fig 2. Experimental design.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4633056/bin/pone.0140967.g002.jpg)
![Fig 3. No-treatment group.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4633056/bin/pone.0140967.g003.jpg)
![Fig 4. Means ( + SD) for…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4633056/bin/pone.0140967.g004.jpg)
Fig 5. Means ( + SD) for…
Fig 5. Means ( + SD) for all the measurements in the aspirin group.
After aspirin administration…
Fig 6. Means ( + SD) for…
Fig 6. Means ( + SD) for all the measurements in the mixed group.
After oxygen administration…
Fig 7. Differences of the means and…
Fig 7. Differences of the means and 95% CI for all the parameters analyzed in…
Fig 8. Model that explains the findings…
Fig 8. Model that explains the findings of the present study.
The repeated association between…
- Nocebo and placebo modulation of hypobaric hypoxia headache involves the cyclooxygenase-prostaglandins pathway.Benedetti F, Durando J, Vighetti S. Benedetti F, et al. Pain. 2014 May;155(5):921-928. doi: 10.1016/j.pain.2014.01.016. Epub 2014 Jan 21. Pain. 2014. PMID: 24462931
- Permeability of brain structures and other peripheral tissues to prostaglandins D2, E2 and F2 alpha in rats.Eguchi N, Kaneko T, Urade Y, Hayashi H, Hayaishi O. Eguchi N, et al. J Pharmacol Exp Ther. 1992 Sep;262(3):1110-20. J Pharmacol Exp Ther. 1992. PMID: 1527717
- High-altitude headache: the effects of real vs sham oxygen administration.Benedetti F, Durando J, Giudetti L, Pampallona A, Vighetti S. Benedetti F, et al. Pain. 2015 Nov;156(11):2326-2336. doi: 10.1097/j.pain.0000000000000288. Pain. 2015. PMID: 26164587 Clinical Trial.
- Thromboxane A2, prostacyclin and aspirin: effects on vascular tone and platelet aggregation.Smith JB, Araki H, Lefer AM. Smith JB, et al. Circulation. 1980 Dec;62(6 Pt 2):V19-25. Circulation. 1980. PMID: 7002350 Review.
- Placebo analgesia.Benedetti F. Benedetti F. Neurol Sci. 2006 May;27 Suppl 2:S100-2. doi: 10.1007/s10072-006-0580-4. Neurol Sci. 2006. PMID: 16688609 Review.
- Clinical Effectiveness and Efficacy of Chiropractic Spinal Manipulation for Spine Pain.Gevers-Montoro C, Provencher B, Descarreaux M, Ortega de Mues A, Piché M. Gevers-Montoro C, et al. Front Pain Res (Lausanne). 2021 Oct 25;2:765921. doi: 10.3389/fpain.2021.765921. eCollection 2021. Front Pain Res (Lausanne). 2021. PMID: 35295422 Free PMC article. Review.
- What is the relative contribution of biological and psychosocial factors to the generation of hypoxia headache?Barbiani D, Camerone E, Benedetti F. Barbiani D, et al. Can J Pain. 2018 Jun 22;2(1):160-168. doi: 10.1080/24740527.2018.1478224. eCollection 2018. Can J Pain. 2018. PMID: 35005376 Free PMC article.
- The Illness Belief Network Questionnaire: Development and Evaluation of a Psychosomatic Assessment Tool.Goli F, Roohafza H, Feizi A, Gholamrezaei A, Farzanegan M, Hashemi M, Kube T, Rief W. Goli F, et al. Iran J Psychiatry. 2021 Apr;16(2):177-186. doi: 10.18502/ijps.v16i2.5819. Iran J Psychiatry. 2021. PMID: 34221044 Free PMC article.
- Placebo Effect of Caffeine on Substrate Oxidation during Exercise.Gutiérrez-Hellín J, Ruiz-Moreno C, Aguilar-Navarro M, Muñoz A, Varillas-Delgado D, Amaro-Gahete FJ, Roberts JD, Del Coso J. Gutiérrez-Hellín J, et al. Nutrients. 2021 Feb 27;13(3):782. doi: 10.3390/nu13030782. Nutrients. 2021. PMID: 33673567 Free PMC article. Clinical Trial.
- Carbohydrate Mouth Rinse Mitigates Mental Fatigue Effects on Maximal Incremental Test Performance, but Not in Cortical Alterations.Brietzke C, Franco-Alvarenga PE, Canestri R, Goethel MF, Vínicius Í, Painelli VS, Santos TM, Hettinga FJ, Pires FO. Brietzke C, et al. Brain Sci. 2020 Jul 29;10(8):493. doi: 10.3390/brainsci10080493. Brain Sci. 2020. PMID: 32751162 Free PMC article.
-
- De Craen AJM, Tijssen JGP, de Gans J, Kleijnen J. Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos. J Neurol 2000;247:183–88. - PubMed
- Randomized Controlled Trial
- Research Support, Non-U.S. Gov't
- Adult
- Dinoprost / blood
- Dinoprostone / blood
- Epoprostenol / blood
- Female
- Headache / blood*
- Humans
- Hypoxia / blood*
- Male
- Oxygen / blood*
- Prostaglandin D2 / blood
- Thromboxane A2 / blood
- Thromboxane A2
- Dinoprost
- Epoprostenol
- Dinoprostone
- Prostaglandin D2
- Oxygen
- Full Text Sources
- Other Literature Sources
- Medical
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![Fig 5. Means ( + SD) for…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4633056/bin/pone.0140967.g005.jpg)
Fig 6. Means ( + SD) for…
Fig 6. Means ( + SD) for all the measurements in the mixed group.
After oxygen administration…
Fig 7. Differences of the means and…
Fig 7. Differences of the means and 95% CI for all the parameters analyzed in…
Fig 8. Model that explains the findings…
Fig 8. Model that explains the findings of the present study.
The repeated association between…
- Nocebo and placebo modulation of hypobaric hypoxia headache involves the cyclooxygenase-prostaglandins pathway.Benedetti F, Durando J, Vighetti S. Benedetti F, et al. Pain. 2014 May;155(5):921-928. doi: 10.1016/j.pain.2014.01.016. Epub 2014 Jan 21. Pain. 2014. PMID: 24462931
- Permeability of brain structures and other peripheral tissues to prostaglandins D2, E2 and F2 alpha in rats.Eguchi N, Kaneko T, Urade Y, Hayashi H, Hayaishi O. Eguchi N, et al. J Pharmacol Exp Ther. 1992 Sep;262(3):1110-20. J Pharmacol Exp Ther. 1992. PMID: 1527717
- High-altitude headache: the effects of real vs sham oxygen administration.Benedetti F, Durando J, Giudetti L, Pampallona A, Vighetti S. Benedetti F, et al. Pain. 2015 Nov;156(11):2326-2336. doi: 10.1097/j.pain.0000000000000288. Pain. 2015. PMID: 26164587 Clinical Trial.
- Thromboxane A2, prostacyclin and aspirin: effects on vascular tone and platelet aggregation.Smith JB, Araki H, Lefer AM. Smith JB, et al. Circulation. 1980 Dec;62(6 Pt 2):V19-25. Circulation. 1980. PMID: 7002350 Review.
- Placebo analgesia.Benedetti F. Benedetti F. Neurol Sci. 2006 May;27 Suppl 2:S100-2. doi: 10.1007/s10072-006-0580-4. Neurol Sci. 2006. PMID: 16688609 Review.
- Clinical Effectiveness and Efficacy of Chiropractic Spinal Manipulation for Spine Pain.Gevers-Montoro C, Provencher B, Descarreaux M, Ortega de Mues A, Piché M. Gevers-Montoro C, et al. Front Pain Res (Lausanne). 2021 Oct 25;2:765921. doi: 10.3389/fpain.2021.765921. eCollection 2021. Front Pain Res (Lausanne). 2021. PMID: 35295422 Free PMC article. Review.
- What is the relative contribution of biological and psychosocial factors to the generation of hypoxia headache?Barbiani D, Camerone E, Benedetti F. Barbiani D, et al. Can J Pain. 2018 Jun 22;2(1):160-168. doi: 10.1080/24740527.2018.1478224. eCollection 2018. Can J Pain. 2018. PMID: 35005376 Free PMC article.
- The Illness Belief Network Questionnaire: Development and Evaluation of a Psychosomatic Assessment Tool.Goli F, Roohafza H, Feizi A, Gholamrezaei A, Farzanegan M, Hashemi M, Kube T, Rief W. Goli F, et al. Iran J Psychiatry. 2021 Apr;16(2):177-186. doi: 10.18502/ijps.v16i2.5819. Iran J Psychiatry. 2021. PMID: 34221044 Free PMC article.
- Placebo Effect of Caffeine on Substrate Oxidation during Exercise.Gutiérrez-Hellín J, Ruiz-Moreno C, Aguilar-Navarro M, Muñoz A, Varillas-Delgado D, Amaro-Gahete FJ, Roberts JD, Del Coso J. Gutiérrez-Hellín J, et al. Nutrients. 2021 Feb 27;13(3):782. doi: 10.3390/nu13030782. Nutrients. 2021. PMID: 33673567 Free PMC article. Clinical Trial.
- Carbohydrate Mouth Rinse Mitigates Mental Fatigue Effects on Maximal Incremental Test Performance, but Not in Cortical Alterations.Brietzke C, Franco-Alvarenga PE, Canestri R, Goethel MF, Vínicius Í, Painelli VS, Santos TM, Hettinga FJ, Pires FO. Brietzke C, et al. Brain Sci. 2020 Jul 29;10(8):493. doi: 10.3390/brainsci10080493. Brain Sci. 2020. PMID: 32751162 Free PMC article.
-
- De Craen AJM, Tijssen JGP, de Gans J, Kleijnen J. Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos. J Neurol 2000;247:183–88. - PubMed
- Randomized Controlled Trial
- Research Support, Non-U.S. Gov't
- Adult
- Dinoprost / blood
- Dinoprostone / blood
- Epoprostenol / blood
- Female
- Headache / blood*
- Humans
- Hypoxia / blood*
- Male
- Oxygen / blood*
- Prostaglandin D2 / blood
- Thromboxane A2 / blood
- Thromboxane A2
- Dinoprost
- Epoprostenol
- Dinoprostone
- Prostaglandin D2
- Oxygen
- Full Text Sources
- Other Literature Sources
- Medical
![Fig 6. Means ( + SD) for…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4633056/bin/pone.0140967.g006.jpg)
Fig 7. Differences of the means and…
Fig 7. Differences of the means and 95% CI for all the parameters analyzed in…
Fig 8. Model that explains the findings…
Fig 8. Model that explains the findings of the present study.
The repeated association between…
![Fig 7. Differences of the means and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4633056/bin/pone.0140967.g007.jpg)
![Fig 8. Model that explains the findings…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4633056/bin/pone.0140967.g008.jpg)
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Source: PubMed