Underappreciated power. Placebo and nocebo in medicine
https://doi.org/10.21518/2079-701X-2020-4-162-167
Abstract
The term placebo is defined as a substance with no therapeutic effect that improves health by convincing the patient that the substance is effective. The term comes from the Latin “placere”, meaning “I will delight” or “do good”. Placebo is a universal tool for evaluating non-medical effects in randomized controlled trials to determine the true pharmacological effect of a drug. Examples of placebo action can be found in any field of medicine, but there is no conceptual basis that integrates it into everyday clinical practice, nor is there a corresponding medical education programme. Three main mechanisms of placebo effect are considered: the expectation model, reflective causality and the neurotransmitter model; it is necessary to take into account that these hypotheses may complement each other.
Nocebo is defined as a substance that has no therapeutic effect, but worsens the condition of the person receiving it because of the negative beliefs and expectations of the person. Nocebo effect, according to several studies, can be modulated by cholecystokinin. There is evidence that cholecystokininin induces hyperalgesia, “turning” anxiety into pain. According to the negative expectation model, nocebo induces hypothalamic-pituitary-adrenal axis, which increases plasma concentrations of adrenocorticotropic hormone and cortisol. Interest in nocebo has increased in recent years due to the introduction of immunobiological biosimilars in clinical practice. There are reports of a higher frequency of drug withdrawal by patients switching from original drugs to biosimilars in open trials compared to blind ones, suggesting a nocebo effect. The conceptual basis of personalized psychopharmacotherapy is to maximize placebo effect and minimize nocebo effect in order to improve treatment outcomes.
About the Author
A. O. Bueverov
Sechenov First Moscow State Medical University (Sechenov University); Moscow Regional Research Clinical Institute named after M.F. Vladimirskiy
Russian Federation
Russian Federation
Alexey O. Bueverov - Dr. of Sci. (Med.), professor, Federal State Autonomous Educational Institution of Higher Education “Sechenov First Moscow State Medical University” of the Ministry of Health of the Russian Federation (Sechenov University); leading researcher, State Budgetary Institution of Healthcare of the Moscow Region “Moscow Regional Research Clinical Institute named after M.F. Vladimirsky”.
8/2, Trubetskaya St., Moscow, 119991; 61/2, Schepkina St., Moscow, 129110.
References
1. Grebenev A.L., Okhlobystin A.V. Powerful placebo. Vrach = The Doctor. 1994;(2):2-5.
2. Pozgain I., Pozgain Z., Degmecic D. Placebo and nocebo effect: a minireview. Psychiatr Danub. 2014;26(2):100-107. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24909245.
3. Jopling D.A. Talking cures and placebo effects. OUP Oxford; 2008. 336 p.
4. Jacobs B. Biblical origins of placebo. J R Soc Med. 2000;93(4):213-214. doi: 10.1177/014107680009300419.
5. Cobb L.A., Thomas G.I., Dillard D.H., Merendino K.A., Bruce R.A. An evolution of internal mammary artery ligation by duble-blind technique. N Engl J Med. 1959;260(22):1115-1118. doi: 10.1056/NEJM195905282602204.
6. Moseley J.B., O'Malley K., Petersen N.J., Menke T.J., Brody B.A., Kuykendall D.H. et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med. 2002;347(2):81-88. doi: 10.1056/NEJMoa013259.
7. Thomas K.B. General practice consultations: is there any point in being positive? Br Med J. 1987;294(6581):1200-1202. doi: 10.1136/bmj.294.6581.1200.
8. Moerman D.E. Edible symbols: the effectiveness of placebos. Ann N Y Acad Sci. 1981;364(1):256-268. doi: 10.1111/j.1749-6632.1981.tb34478.x.
9. Flik C.E., Bakker L., Laan W., van Rood Y.R., Smout A.J., de Wit N.J. Systematic review: the placebo effect of psychological interventions in the treatment of irritable bowel syndrome. World J Gastroenterol. 2017;23(12):2223-2233. doi: 10.3748/wjg.v23.i12.2223.
10. Polich G., Iaccarino M.A., Kaptchuk T.J., Morales-Quezada L., Zafonte R. Placebo effects in traumatic brain injury. J Neurotrauma. 2018;35(11):1205-1212. doi: 10.1089/neu.2017.5506.
11. Benedetti F. Placebo and the new physiology of the doctor-patient relationship. Physiol Rev. 2013;93(3):1207-1246. doi: 10.1152/physrev.00043.2012.
12. Manchikanti L., Giordano J., Fellows B., Hirsch J.A. Placebo and nocebo in interventional pain management: a friend or a foe - or simply foes? Pain Physician. 2011;14(2):157-175. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21412379.
13. Jensen K.B., Kaptchuk T.J., Kirsch I., Raicek J., Lindstrom K.M., Berna Ch. et al. Nonconscious activation of placebo and nocebo pain responses. Proc Natl Acad Sci USA. 2012;109(39):15959-15964. doi: 10.1073/pnas.1202056109.
14. Hall K.T., Loscalzo J., Kaptchuk T. Pharmacogenomics and the placebo response. ACS Chem Neurosci. 2018;9(4):633-635. doi: 10.1021/acschemneuro.8b00078.
15. Kato S. Review of placebo effect and re-evaluation of psychotherapy focusing on depressive disorders. Seishin Shinkeigaku Zasshi. 2013;115(8):887-900. Available at: https://www.ncbi.nlm.nih.gov/pub-med/24167970.
16. Hall K.T., Loscalzo J., Kaptchuk T.J. Genetics and the placebo effect: the placebome. Trends Mol Med. 2015;21(5):285-294. doi: 10.1016/j.mol-med.2015.02.009.
17. Lipton B.H. The biology of belief: unleashing the power of consciousness, matter, & miracles. Carlsbad, Calif.: Hay House; 2007.
18. Kirsch I., Moore T.J., Scoboria A., Nicholls S.S. The Emperor's New Drugs: An Analysis of Antidepressant Medication Data Submitted to the U.S. Food and Drug Administration. Prevention and Treatment. 2002;5(1):23. doi: 10.1037/1522-3736.5.1.523a.
19. Quitkin F.M., Rabkin J.G., Stewart J.W., McGrath P.J., Harrison W., Ross D.C. et al. Heterogenity of clinical response during placebo treatment. Am J Psychiatry. 1991;148(2):193-196. doi: 10.1176/ajp.148.2.193.
20. Agid O., Siu C.O., Potkin S.G., Kapur S., Watsky E., Vanderburg D. et al. Metaregression analysis of placebo response in antipsychotic trials, 1970-2010. Am J Psychiatry. 2013;170:1335-1344. doi: 10.1176/appi.ajp.2013.12030315.
21. Colloca L., Howick J. Placebos without deception: outcomes, mechanisms, and ethics. Int Rev Neurobiol. 2018;138:219-240. doi: 10.1016/bs.irn.2018.01.005.
22. Kube T., Rief W., Vivell M.B., Schafer N.L., Vermillion T., Korfer K., Glombiewski J.A. Deceptive and nondeceptive placebos to reduce pain: an experimental study in healthy individuals. Clin J Pain. 2020;36(2):68-79. doi: 10.1097/AJP.0000000000000781.
23. Kaptchuk T.J., Friedlander E., Kelley J.M., Sanchez M.N., Kokkotou E., Singer J.P. et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS One. 2010;5(12):15591. doi: 10.1371/journal.pone.0015591.
24. Hoenemeyer T.W., Kaptchuk T.J., Mehta T.S., Fontaine K.R. Open-label placebo treatment for cancer-related fatigue: a randomized-controlled clinical trial. Sci Rep. 2018;8(1):2784. doi: 10.1038/s41598-018-20993-y.
25. Corsi N., Emadi Andani M., Tinazzi M., Fiorio M. Changes in perception of treatment efficacy are associated to the magnitude of the nocebo effect and to personality traits. Sci Rep. 2016;6:30671. doi: 10.1038/srep30671.
26. Hauser W., Hansen E., Enck P. Nocebo phenomena in medicine: their relevance in everyday clinical practice. Dtsch Arztebl Int. 2012;109(26):459-465. doi: 10.3238/arztebl.2012.0459.
27. Glintborg B., Sorensen I.J., Loft A.G., Esbesen J., Lindegaard H., Jensen D.V. FRI0190 Clinical outcomes from a nationwide non-medical switch from originator to biosimilar etanercept in patients with inflammatory arthritis after 5 months follow-up. Results from DANBIO registry. Ann Rheum Dis. 2017;76(2):553.2-554. doi: 10.1136/annrheumdis-2017-eular.1703.
28. Odinet J.S., Day C.E., Cruz J.L., Heindel G.A. The biosimilar nocebo effect? A systematic review of double-blinded versus open-label studies. J Manag Care Spec Pharm. 2018;24(10):952-959. doi: 10.18553/jmcp.2018.24.10.952.
29. Colloca L., Panaccione R., Murphy T.K. The clinical implications of nocebo effects for biosimilar therapy. Front Pharmacol. 2019;10:1372. doi: 10.3389/fphar.2019.01372.
30. Nikiphorou E., Kautiainen H., Hannonen P., Asikainen J., Kokko A., Rannio T. Clinical effectiveness of CT-P13 (infliximab biosimilar) used as a switch from Remicade (infliximab) in patients with established rheumatic disease. Report of clinical experience based on prospective observational data. Expert Opin Biol Ther. 2015;15(12):1677-1683. doi: 10.1517/14712598.2015.1103733.
31. Tweehuysen L., van den Bemt B.J.F., van Ingen I.L., de Jong A.J.L., van der Laan W.H., van den Hoogen F.H.J. Subjective complaints as the main reason for biosimilar discontinuation after open-label transition from reference infliximab to biosimilar infliximab. Arthritis Rheumatol. 2018;70(1):60-68. doi: 10.1002/art.40324.
32. Bingel U., Wanigasekera V., Wiech K., Ni Mhuircheartaigh R., Lee M.C., Ploner M., Tracey I. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med. 2011;3(70):70ra14. doi: 10.1126/scitranslmed.3001244.
33. Webster R.K., Weinman J., Rubin G.J. How does the side-effect information in patient information leaflets influence peoples' side-effect expectations? A cross-sectional national survey of 18- to 65-year-olds in England. Health Expect. 2017;20(6):1411-1420. doi: 10.1111/hex.12584.
34. Jakovljevic M. The placebo-nocebo response: controversies and challenges from clinical and research perspective. Eur Neuropsychopharmacol. 2014;24(3):333-341. doi: 10.1016/j.euroneuro.2013.11.014.
35. Liccardi G., Senna G., Russo M., Bonadonna P., Crivellaro M., Dama A. et al. Evaluation of the placebo effect during oral challenge in patients with adverse drug reactions. J Investig Allergol Clin Immunol. 2004;14(2):104-107. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15301298.
36. Verhulst J., Kramer D., Swan A.C., Hale-Richlen B., Beahrs J. The medical alliance: from placebo response to alliance effect. J Nerv Ment Dis. 2013;201:546-552. doi: 10.1097/NMD.0b013e31829829e1.
37. Macklin R. The Declaration of Helsinki: another revision. Indian J Med Ethics. 2009;6(1):2-4. doi: 10.20529/IJME.2009.001.
38. Blease C., Colloca L., Kaptchuk T.J. Are open-label placebos ethical? Informed consent and ethical equivocations. Bioethics. 2016;30(6):407-414. doi: 10.1111/bioe.12245.
39. Llanos L., Moreu R., Ortin T., Peiro A.M., Pascual S., Bellot P.et al. The existence of a relationship between increased serum alanine aminotransferase levels detected in premarketing clinical trials and postmarketing published hepatotoxicity case reports. Aliment Pharmacol Ther. 2010;31(12):1337-1345. doi: 10.1111/j.1365-2036.2010.04298.x.
Review
For citations:
Bueverov AO. Underappreciated power. Placebo and nocebo in medicine. Meditsinskiy sovet = Medical Council. 2020;(4):162-167. (In Russ.) https://doi.org/10.21518/2079-701X-2020-4-162-167
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