The fallacy of the placebo-controlled clinical trials: Are positive outcomes the result of ‘indirect’ treatment effects?
DOI:
https://doi.org/10.15540/nr.4.3-4.102Keywords:
placebo, nocebo, active placebo, clinical trials, depressionAbstract
This paper argues that placebo effects have a larger influence and may better explain clinical trial outcomes compared to purported treatment effects currently attributed to clinical treatments. Placebo-controlled clinical trials usually do not include an ‘active’ placebo and thus the clinical outcome could be due to the placebo responses induced by the non-therapeutic side effects of the treatment. For this paper, an active placebo includes substances or procedures that permits attribution of a physiological effect such as a B-vitamin that safely causes flushing as well as a biofeedback training procedure that safely trains physiological responses other than the target response. The paper also discusses the positive outcome of a sham treatment procedure in contrast to the nocebo effect. This paper emphasizes exercising caution when interpreting clinical trials of pharmaceutical or surgical treatments. The paper discusses possible mechanisms underlying the acceptance of treatment procedures which later have been shown to be ineffective or harmful, and highlights the importance of incorporating active placebo procedures to address any covert treatment side effects induced by placebo response. Finally, this paper argues that clinical trials of bio/neurofeedback treatments carefully consider the important and consequential influences of placebos when interpreting the results of trial outcomes.
References
Angell, M. (2009). Drug companies & doctors: A story of corruption. The New York Review of Books, 56(1), 8-12. Available: http://www.nybooks.com/articles/archives/2009/jan/15/drug-companies-doctorsa-story-of-corruption/. Accessed 24, November, 2016.
Autier, P., Boniol, M., Gavin, A., & Vatten, L. J. (2011). Breast cancer mortality in neighbouring European countries with different levels of screening but similar access to treatment: trend analysis of WHO mortality database. Bmj, 343, d4411. http://dx.doi.org/ doi.org/10.1136/bmj.d4411
Ballenger, J. C., Burrows, G. D., DuPont, R. L., Lesser, I. M., Noyes, R., Pecknold, J. C., & Swinson, R. P. (1988). Alprazolam in panic disorder and agoraphobia: Results from a multicenter trial: I. Efficacy in short-term treatment. Archives of general psychiatry, 45(5), 413-422. doi:10.1001/archpsyc.1988.01800290027004
Babyak, M., Blumenthal, J. A., Herman, S., Khatri, P., Doraiswamy, M., Moore, K., ... & Krishnan, K. R. (2000). Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosomatic medicine, 62(5), 633-638.
Beecher, H.K. (1961). Surgery as Placebo. JAMA, 176(13), 1102-1107. doi:10.1001/jama.1961.63040260007008
Bell, R. M., Rear, R., Cunningham, J., Dawnay, A., & Yellon, D. M. (2014). Effect of remote ischaemic conditioning on contrast-induced nephropathy in patients undergoing elective coronary angiography (ERICCIN): rationale and study design of a randomised single-centre, double-blind placebo-controlled trial. Clinical Research in Cardiology, 103(3), 203-209. doi:10.1007/s00392-013-0637-3
Benedetti, F. (2007). The Placebo and Nocebo Effect: How the Therapist’s Words Act on the Patient’s Brain. Karger Gazette, 69. http://misc.karger.com/gazette/69/benedetti/art_3.htm
Bisson, J. I., Jenkins, P. L., Alexander, J., & Bannister, C. (1997). Randomised controlled trial of psychological debriefing for victims of acute burn trauma. The British journal of psychiatry, 171(1), 78-81. doi:10.1192/bjp.171.1.78
Bok, S. (2013). The ethics of giving placebos. In: Miller, F. G., Colloca, L., & Kaptchuk, T. J. (Eds.). The placebo: A reader (pp. 296-300). JHU Press.
Bollen, K. A., & Diamantopoulos, A. (2017). In defense of causal-formative indicators: A minority report. Psychological Methods, 22(3), 581. http://dx.doi.org/10.1037/met0000056
Bollen, K. A., & Pearl, J. (2013). Eight myths about causality and structural equation models. In Handbook of causal analysis for social research (pp. 301-328). Springer Netherlands. doi:10.1007/978-94-007-6094-3 15
Bjørkedal, E. (2016). Active Placebo-The relation of treatment expectancies to active analgesic treatments. http://hdl.handle.net/10037/10017
Brabant, O. (2016). More than meets the eye: toward a post-materialist model of consciousness. EXPLORE: The Journal of Science and Healing, 12(5), 347-354. http://dx.doi.org/10.1016/j.explore.2016.06.006
Branthwaite A, Cooper, P. (1981). Analgesic effects of branding in treatment of headaches. Br Med J Clin Res Ed. 282, 1576-1578. http://dx.doi.org/10.1136/bmj.282.6276.1576
Brignardello-Petersen R, Guyatt GH, Buchbinder R, et al. (2017). Knee arthroscopy versus conservative management in patients with degenerative knee disease: a systematic review. BMJ Open.(7):e016114. doi:10.1136/bmjopen-2017- 016114
Brown, L. A., LeBeau, R., Liao, B., Niles, A. N., Glenn, D., & Craske, M. G. (2016). A comparison of the nature and correlates of panic attacks in the context of Panic Disorder and Social Anxiety Disorder. Psychiatry research, 235, 69-76. http://dx.doi.org/10.1016/j.psychres.2015.11.048
Carey, J. L., Nader, N., Chai, P. R., Carreiro, S., Griswold, M. K., & Boyle, K. L. (2017). Drugs and Medical Devices: Adverse Events and the Impact on Women’s Health. Clinical Therapeutics. http://dx.doi.org/10.1016/j.clinthera.2016.12.009
Cobb, L. A., Thomas, G. I., Dillard, D. H., Merendino, K. A., & Bruce, R. A. (1959). An evaluation of internal-mammary-artery ligation by a double-blind technic. New England Journal of Medicine, 260(22), 1115-1118. doi:10.1056/NEJM195905282602204
Cohen, S. (2014). The nocebo effect of informed consent. Bioethics, 28(3), 147-154. doi:10.1111/j.1467-8519.2012.01983.x
Colloca L, Benedetti F. (2005). Placebos and painkillers: is mind as real as matter? Nat Rev Neurosci. 6, 545-552. doi:1038/nrn1705
Colloca, L., & Finniss, D. (2012). Nocebo effects, patient-clinician communication, and therapeutic outcomes. Jama, 307(6), 567-568. doi:10.1001/jama.2012.115
Colloca, L., Pine, D. S., Ernst, M., Miller, F. G., & Grillon, C. (2016). Vasopressin boosts placebo analgesic effects in women: a randomized trial. Biological psychiatry, 79(10), 794-802. doi: 10.1016/j.biopsych.2015.07.019
Department of Justice. (2012). http://www.justice.gov/opa/pr/glaxosmithkline-plead-guilty-and-pay-3-billion-resolve-fraud-allegations-and-failure-report
Dispenza, J. (2014). You are the placebo: Making your mind matter. Hay House, Inc.
Doering, B. K., Rief, W., & Petrie, K. J. (2014). Lessons to be learned from placebo arms in psychopharmacology trials. In Placebo (pp. 273-290). Springer Berlin Heidelberg. doi:10.1007/978-3-662-44519-8
Enck, P., Bingel, U., Schedlowski, M., & Rief, W. (2013). The placebo response in medicine: minimize, maximize or personalize?. Nature reviews Drug discovery, 12(3), 191-204. doi:10.1038/nrd3923
Every‐Palmer, S., & Howick, J. (2014). How evidence‐based medicine is failing due to biased trials and selective publication. Journal of evaluation in clinical practice, 20(6), 908-914. doi:10.1111/jep.12147
Felson, D. T., & Buckwalter, J. (2002). Debridement and lavage for osteoarthritis of the knee. doi:10.1056/NEJMe020055
Franco, A., Malhotra, N., & Simonovits, G. (2014). Publication bias in the social sciences: Unlocking the file drawer. Science, 345(6203), 1502-1505. doi:10.1126/science.1255484
Friedman, L., & Friedman, M. (2016). Financial conflicts of interest and study results in environmental and occupational health research. Journal of Occupational and Environmental Medicine, 58(3), 238-247. doi:10.1097/JOM.0000000000000671
Greenstone, G. (2010). The history of bloodletting. BC Medical Journal, 52(1), 12-14. http://www.bcmj.org/premise/history-bloodletting
Hallgren, M., Herring, M. P., Owen, N., Dunstan, D., Ekblom, Ö., Helgadottir, B., ... & Forsell, Y. (2016). Exercise, physical activity, and sedentary behavior in the treatment of depression: broadening the scientific perspectives and clinical opportunities. Frontiers in psychiatry, 7. doi: 10.3389/fpsyt.2016.00036
Haanstra, T. M., Kamper, S. J., Williams, C. M., Spriensma, A. S., Lin, C. W. C., Maher, C. G., & Ostelo, R. W. (2015). Does adherence to treatment mediate the relationship between patients' treatment outcome expectancies and the outcomes of pain intensity and recovery from acute low back pain?. Pain, 156(8), 1530-1536.
doi:10.1097/j.pain.0000000000000198
Horton, R. (2015). Offline: What is medicine’s 5 sigma. The Lancet, 385(9976), 1380. http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736%2815%2960696-1.pdf
Howick, J. (2017). The relativity of ‘placebos’: defending a modified version of Grünbaum’s definition. Synthese, 194(4), 1363-1396. doi:10.1007/s11229-015-1001-0
Howick, J., Friedemann, C., Tsakok, M., Watson, R., Tsakok, T., Thomas, J., ... & Heneghan, C. (2013). Are treatments more effective than placebos? A systematic review and meta-analysis. PloS one, 8(5), e62599. http://dx.doi.org/10.1371/journal.pone.0062599
Jensen, J. S., Bielefeldt, A. Ø., & Hróbjartsson, A. (2017). Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration: A methodological overview. Journal of Clinical Epidemiology. http://dx.doi.org/10.1016/j.jclinepi.2017.03.001
Johnson, P. L., Federici, L. M., & Shekhar, A. (2014). Etiology, triggers and neurochemical circuits associated with unexpected, expected, and laboratory-induced panic attacks. Neuroscience & Biobehavioral Reviews, 46, 429-454. http://dx.doi.org/10.1016/j.neubiorev.2014.07.027
Johnston, J. C., Wester, K., & Sartwelle, T. P. (2016). Neurological fallacies leading to malpractice: a case studies approach. Neurologic clinics, 34(3), 747-773. http://dx.doi.org/10.1016/j.ncl.2016.04.011
Jonas, W. B., Crawford, C., Colloca, L., Kaptchuk, T. J., Moseley, B., Miller, F. G., & Meissner, K. (2015). To what extent are surgery and invasive procedures effective beyond a placebo response? A systematic review with meta-analysis of randomised, sham controlled trials. BMJ open, 5(12), e009655. http://dx.doi.org/10.1136/bmjopen-2015-009655
Kassin, S. M., Dror, I. E., & Kukucka, J. (2013). The forensic confirmation bias: Problems, perspectives, and proposed solutions. Journal of Applied Research in Memory and Cognition, 2(1), 42-52. http://dx.doi.org/10.1016/j.jarmac.2013.01.001
Kirkley, A., Birmingham, T. B., Litchfield, R. B., Giffin, J. R., Willits, K. R., Wong, C. J., ... & Pope, J. E. (2008). A randomized trial of arthroscopic surgery for osteoarthritis of the knee. New England Journal of Medicine, 359(11), 1097-1107. doi:10.1056/NEJMoa0708333
Kirsch, I. (2014). The emperor’s new drugs: medication and placebo in the treatment of depression. In Placebo (pp. 291-303). Springer Berlin Heidelberg. doi:10.1007/978-3-662-44519-8
Kirsch, I., & Sapirstein, G. (1998). Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication. http://dx.doi.org/10.1037/1522-3736.1.1.12a
Lee, L. (2015). Is Caffeine Effective In Reducing Pain Perception During Exercise Performance In Healthy Adults? http://digitalcommons.pcom.edu/pa_systematic_reviews
Leichsenring, F., Abbass, A., Hilsenroth, M. J., Leweke, F., Luyten, P., Keefe, J. R., & Steinert, C. (2017). Biases in research: risk factors for non-replicability in psychotherapy and pharmacotherapy research. Psychological medicine, 47(6), 1000-1011.
http://dx.doi.org/10.1017/S003329171600324X
Le Noury, J., Nardo, J. M., Healy, D., Jureidini, J., Raven, M., Tufanaru, C., & Abi-Jaoude, E. (2015). Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. bmj, 351, h4320. http://dx.doi.org/10.1136/bmj.h4320
Lindsley, C. W. (2015). 2013 Trends and Statistics for Prescription Medications in the United States: CNS Highest Ranked and Record Number of Prescriptions Dispensed. doi:10.1021/acschemneuro.5b00049
Loannidis, J. P. (2005). Why most published research findings are false. PLos med, 2(8), e124. http://dx.doi.org/10.1371/journal.pmed.0020124
Lucas, V., & Booth, S. (2014). The importance of placebo effects in enhancing palliative care interventions. BMJ supportive & palliative care, bmjspcare-2013. http://dx.doi.org/10.1136/bmjspcare-2013-000571
Luctkar-Flude, M., Groll, D., & Tyerman, J. (2017). Using neurofeedback to manage long-term symptoms in cancer survivors: Results of a survey of neurofeedback providers. European Journal of Integrative Medicine. http://dx.doi.org/10.1016/j.eujim.2017.06.003
Mayberg, H. S., Silva, J. A., Brannan, S. K., Tekell, J. L., Mahurin, R. K., McGinnis, S., & Jerabek, P. A. (2002). The functional neuroanatomy of the placebo effect. American Journal of Psychiatry, 159(5), 728-737. http://dx.doi.org/10.1176/appi.ajp.159.5.728
Mayou, RA. Ehlers AA, Hobbs MM. (2000). Psychological debriefing for road traffic accident victims: three-year follow-up of a randomised controlled trial. Br J Psychiatry, 176, 589–593. doi:10.1192/bjp.176.6.589
McBride, W. G. (1961). Thalidomide and congenital abnormalities. The Lancet, 278(7216), 1358. http://dx.doi.org/10.1016/S0140-6736(61)90927-8
Moerman, D.E., Jonas, W.B. (2002).Deconstructing the Placebo Effect and Finding the Meaning Response. Annals of Internal Medicine. 136 (6), 471-476. doi:10.7326/0003-4819-136-6-200203190-00011
Monk, P., Garfjeld Roberts, P., Palmer, A. J., Bayliss, L., Mafi, R., Beard, D., ... & Price, A. (2017). The urgent need for evidence in arthroscopic meniscal surgery: a systematic review of the evidence for operative management of meniscal tears. The American journal of sports medicine, 45(4), 965-973. doi:10.1177/0363546516650180
Mora, M. S. (2011). Lessons learned from placebo groups in antidepressant trials. Philosophical Transactions of the Royal Society B: Biological Sciences 366 (1572) 1879-1888. doi: 10.1098/rstb.2010.0394
Moseley, J.B., et al, (2002). A controlled trial of arthroscopic surgery for osteoarthritis of the knee. New England Journal of Medicine. 347(2), 81-88. doi:10.1056/NEJMoa013259
Nelson, H. D., Tyne, K., Naik, A., Bougatsos, C., Chan, B., & Nygren, P. (2014). Screening for Breast Cancer: Systematic Evidence Review Update for the US Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2009. doi: 10.1059/0003-4819-151-10-200911170-00009
Ornish, D., Brown, S. E., Scherwitz, L. W., Billings, J. H., Armstrong, W. T., Ports, T. A., et al. (1990). Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. The Lancet, 336, 129 –133. http://dx.doi.org/10.1016/0140-6736(90)91656-U
Ornish, D., Scherwitz, L. W., Billings, J. H., Brown, S. E., Gould, K. L., Merritt, T. A., et al. (1998). Intensive lifestyle changes for reversal of coronoary disease. Journal of the American Medical Association, 280, 2001–2007. doi:10.1001/jama.280.23.2001
Pecknold, J. C., Swinson, R. P., Kuch, K., & Lewis, C. P. (1988). Alprazolam in panic disorder and agoraphobia: Results from a multicenter trial: III. Discontinuation effects. Archives of General Psychiatry, 45(5), 429-436. doi:10.1001/archpsyc.1988.01800290043006
Pischke, C. R., Scherwitz, L., Weidner, G., & Ornish, D. (2008). Long-term effects of lifestyle changes on well-being and cardiac variables among coronary heart disease patients. Health psychology, 27(5), 584. http://dx.doi.org/10.1037/0278-6133.27.5.584
Planès, S., Villier, C., & Mallaret, M. (2016). The nocebo effect of drugs. Pharmacology research & perspectives, 4(2). doi:10.1002/prp2.208
Pollan, M. (2015). The trip treatment. The New Yorker, New York, 9.
http://video.newyorker.com/watch/a-reporter-at-largemagic-mushrooms-and-the-healing-trip-2015-02-02
Rogel, A., Guez, J., Getter, N., Keha, E., Cohen, T., Amor, T., & Todder, D. (2015). Transient Adverse Side Effects During Neurofeedback Training: A Randomized, Sham-Controlled, Double Blind Study. Applied psychophysiology and biofeedback, 40(3), 209-218. doi:10.1007/s10484-015-9289-6
Roose, S. P., Rutherford, B. R., Wall, M. M., & Thase, M. E. (2016). Practising evidence-based medicine in an era of high placebo response: number needed to treat reconsidered. The British Journal of Psychiatry, 208(5), 416-420. doi:10.1192/bjp.bp.115.163261
Rosendahl, J., Koranyi, S., Jacob, D., Zech, N., & Hansen, E. (2016). Efficacy of therapeutic suggestions under general anesthesia: a systematic review and meta-analysis of randomized controlled trials. BMC anesthesiology, 16(1), 125. http://dx. http://dx.doi.org/10.1186/s12871-016-0292-0
Ruan, X., & Kaye, A. D. (2016). Nocebo Effect of Informed Consent in Interventional Procedures. Clinical Journal of Pain, 32(5), 460–462.
doi:10.1097/AJP.0000000000000332
Salzman, C., & Shader, R. I. (2015). Not again: benzodiazepines once more under attack. Journal of Clinical Psychopharmacology, 35(5), 493–495.
doi:10.1097/JCP.0000000000000383
Schweiger, A., & Parducci, A. (1981). Nocebo: the psychologic induction of pain. Integrative Physiological and Behavioral Science, 16(3), 140-143. http://dx.doi.org/10.1007/BF03003218
Schwarz, K. A., & Büchel, C. (2015). Cognition and the placebo effect–dissociating subjective perception and actual performance. PloS one, 10(7), e0130492. http://dx.doi.org/10.1371/journal.pone.0130492
Sellaro, R., Güroǧlu, B., Nitsche, M. A., van den Wildenberg, W. P., Massaro, V., Durieux, J., & Colzato, L. S. (2015). Increasing the role of belief information in moral judgments by stimulating the right temporoparietal junction. Neuropsychologia, 77, 400-408. http://dx.doi.org/10.1016/j.neuropsychologia.2015.09.016
Shader, R. I. (2017). Placebos, Active Placebos, and Clinical Trials. Clinical Therapeutics, 39(3), 451–454. http://dx.doi.org/10.1016/j.clinthera.2017.02.001
Stamatakis, E., Weiler, R., & Ioannidis, J. (2013). Undue industry influences that distort healthcare research, strategy, expenditure and practice: a review. European journal of clinical investigation, 43(5), 469-475. doi:10.1111/eci.12074
Stewart-Williams, S., & Podd, J. (2004). The placebo effect: dissolving the expectancy versus conditioning debate. Psychological bulletin, 130(2), 324. doi:10.1037/0033-2909.130.2.324
Taleb, N. N. (2012). Antifragile: Things that gain from disorder (Vol. 3). Random House.
Taubes, G. (2016). The Case Against Sugar. Portobello Books.
Thomas, R., Williams, M., Sharma, H., Chaudry, A., & Bellamy, P. (2014). A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer—the UK NCRN Pomi-T study. Prostate cancer and prostatic diseases, 17(2), 180-186. doi:10.1038/pcan.2014.6
van Dixhoorn, J., & White, A. (2005). Relaxation therapy for rehabilitation and prevention in ischaemic heart disease: a systematic review and meta-analysis. European Journal of Cardiovascular Prevention & Rehabilitation, 12(3), 193-202. http://www.euronet.nl/users/dixhoorn/review.pdf
Vaughn, F., Wichowski, H., & Bosworth, G. (2007). Does preoperative anxiety level predict postoperative pain?. AORN journal, 85(3), 589-604. http://dx.doi.org/10.1016/S0001-2092(07)60130-6
Vineberg, A., & Miller, G. (1951). Treatment of coronary insufficiency. Canadian Medical Association Journal, 64(3), 204. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1821866/pdf/canmedaj00654-0019.pdf
Vollebregt, M. A., Dongen‐Boomsma, M., Buitelaar, J. K., & Slaats‐Willemse, D. (2014). Does EEG‐neurofeedback improve neurocognitive functioning in children with attention‐deficit/hyperactivity disorder? A systematic review and a double‐blind placebo‐controlled study. Journal of Child Psychology and Psychiatry, 55(5), 460-472. doi:10.1111/jcpp.12143
Zbuk, K., & Anand, S. S. (2012). Declining incidence of breast cancer after decreased use of hormone-replacement therapy: magnitude and time lags in different countries. Journal of epidemiology and community health, 66(1), 1-7. http://dx.doi.org/10.1136/jech.2008.083774
Downloads
Published
Issue
Section
License
Authors who publish with this journal agree to the following terms:- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License (CC-BY) that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).