Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

The placebo response in medicine: minimize, maximize or personalize?

Abstract

Our understanding of the mechanisms mediating or moderating the placebo response to medicines has grown substantially over the past decade and offers the opportunity to capitalize on its benefits in future drug development as well as in clinical practice. In this article, we discuss three strategies that could be used to modulate the placebo response, depending on which stage of the drug development process they are applied. In clinical trials the placebo effect should be minimized to optimize drug–placebo differences, thus ensuring that the efficacy of the investigational drug can be truly evaluated. Once the drug is approved and in clinical use, placebo effects should be maximized by harnessing patients' expectations and learning mechanisms to improve treatment outcomes. Finally, personalizing placebo responses — which involves considering an individual's genetic predisposition, personality, past medical history and treatment experience — could also maximize therapeutic outcomes.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mediation of placebo responses by cognitive factors and behavioural conditioning with pharmacological stimuli.
Figure 2: Design features to illustrate and control components of the placebo effect in clinical trials.
Figure 3: Is there an optimal window for the detection of drug–placebo differences?
Figure 4: What are the features of an ideal study design?

Similar content being viewed by others

References

  1. Bingel, U. et al. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci. Transl. Med. 3, 70ra14 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Colloca, L. & Benedetti, F. Placebos and painkillers: is mind as real as matter? Nature Rev. Neurosci. 6, 545–552 (2005).

    Article  CAS  Google Scholar 

  3. Doering, B. K. & Rief, W. Utilizing placebo mechanisms for dose reduction in pharmacotherapy. Trends Pharmacol. Sci. 33, 165–172 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Kaptchuk, T. J. et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ 336, 999–1003 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  5. [No authors listed.] An Audience With... Ted Kaptchuk. Nature Rev. Drug Discov. 7, 554 (2008).

  6. Benedetti, F. Placebo Effects: Understanding the mechanisms in health and disease (Oxford Univ. Press, 2008).

    Book  Google Scholar 

  7. Fields, H. State-dependent opioid control of pain. Nature Rev. Neurosci. 5, 565–575 (2004).

    Article  CAS  Google Scholar 

  8. Millan, M. J. Descending control of pain. Prog. Neurobiol. 66, 355–474 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Eippert, F., Finsterbusch, J., Bingel, U. & Buchel, C. Direct evidence for spinal cord involvement in placebo analgesia. Science 326, 404 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Amanzio, M. & Benedetti, F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J. Neurosci. 19, 484–494 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Benedetti, F., Amanzio, M., Rosato, R. & Blanchard, C. Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nature Med. 17, 1228–1230 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Eippert, F. et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 63, 533–543 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Wager, T. D., Scott, D. J. & Zubieta, J. K. Placebo effects on human μ-opioid activity during pain. Proc. Natl Acad. Sci. USA 104, 11056–11061 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Guo, J. Y., Wang, J. Y. & Luo, F. Dissection of placebo analgesia in mice: the conditions for activation of opioid and non-opioid systems. J. Psychopharmacol. 24, 1561–1567 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Levine, J. D., Gordon, N. C. & Fields, H. L. The mechanism of placebo analgesia. Lancet 2, 654–657 (1978).

    Article  CAS  PubMed  Google Scholar 

  16. Tracey, I. Getting the pain you expect: mechanisms of placebo, nocebo and reappraisal effects in humans. Nature Med. 16, 1277–1283 (2010).

    Article  CAS  PubMed  Google Scholar 

  17. de la Fuente-Fernandez, R. et al. Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease. Science 293, 1164–1166 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Lidstone, S. C. et al. Effects of expectation on placebo-induced dopamine release in Parkinson disease. Arch. Gen. Psychiatry 67, 857–865 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. Leuchter, A. F., Cook, I. A., Witte, E. A., Morgan, M. & Abrams, M. Changes in brain function of depressed subjects during treatment with placebo. Am. J. Psychiatry 159, 122–129 (2002).

    Article  PubMed  Google Scholar 

  20. Mayberg, H. S. et al. The functional neuroanatomy of the placebo effect. Am. J. Psychiatry 159, 728–737 (2002).

    Article  PubMed  Google Scholar 

  21. Petrovic, P. et al. Placebo in emotional processing-induced expectations of anxiety relief activate a generalized modulatory network. Neuron 46, 957–969 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Furmark, T. et al. A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety. J. Neurosci. 28, 13066–13074 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ader, R. & Cohen, N. Behaviorally conditioned immunosuppression. Psychosom. Med. 37, 333–340 (1975).

    Article  CAS  PubMed  Google Scholar 

  24. Goebel, M. U. et al. Behavioral conditioning of immunosuppression is possible in humans. FASEB J. 16, 1869–1873 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Goebel, M. U., Meykadeh, N., Kou, W., Schedlowski, M. & Hengge, U. R. Behavioral conditioning of antihistamine effects in patients with allergic rhinitis. Psychother. Psychosom. 77, 227–234 (2008).

    Article  PubMed  Google Scholar 

  26. Schedlowski, M. & Pacheco-Lopez, G. The learned immune response: Pavlov and beyond. Brain Behav. Immun. 24, 176–185 (2010).

    Article  PubMed  Google Scholar 

  27. Wirth, T. et al. Repeated recall of learned immunosuppression: evidence from rats and men. Brain Behav. Immun. 25, 1444–1451 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Benedetti, F. et al. Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses. J. Neurosci. 23, 4315–4323 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sabbioni, M. E. et al. Classically conditioned changes in plasma cortisol levels induced by dexamethasone in healthy men. FASEB J. 11, 1291–1296 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Benedetti, F. The Patient's Brain: The neuroscience behind the doctor–patient relationship (Oxford Univ. Press, 2011).

    Google Scholar 

  31. Rief, W., Bingel, U., Schedlowski, M. & Enck, P. Mechanisms involved in placebo and nocebo responses and implications for drug trials. Clin. Pharmacol. Ther. 90, 722–726 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Hill, A. B. Suspended judgement. Memories of the British streptomycin trial in tuberculosis. The first randomized clinical trial. Control. Clin. Trials 11, 77–79 (1990).

    Article  CAS  PubMed  Google Scholar 

  33. Diener, H. C., Dowson, A. J., Ferrari, M., Nappi, G. & Tfelt-Hansen, P. Unbalanced randomization influences placebo response: scientific versus ethical issues around the use of placebo in migraine trials. Cephalalgia 19, 699–700 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Papakostas, G. I. & Fava, M. Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Eur. Neuropsychopharmacol. 19, 34–40 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Mallinckrodt, C. H., Zhang, L., Prucka, W. R. & Millen, B. A. Signal detection and placebo response in schizophrenia: parallels with depression. Psychopharmacol. Bull. 43, 53–72 (2010).

    PubMed  Google Scholar 

  36. Sinyor, M. et al. Does inclusion of a placebo arm influence response to active antidepressant treatment in randomized controlled trials? Results from pooled and meta-analyses. J. Clin. Psychiatry 71, 270–279 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Nakamura, Y. et al. Investigating dose-dependent effects of placebo analgesia: a psychophysiological approach. Pain 153, 227–237 (2012).

    Article  PubMed  Google Scholar 

  38. Rutherford, B. R., Sneed, J. R. & Roose, S. P. Does study design influence outcome? The effects of placebo control and treatment duration in antidepressant trials. Psychother. Psychosom. 78, 172–181 (2009).

    Article  PubMed  Google Scholar 

  39. Quigley, E. M. et al. Randomised clinical trials: linaclotide phase 3 studies in IBS-C — a prespecified further analysis based on European Medicines Agency-specified endpoints. Aliment. Pharmacol. Ther. 37, 49–61 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Staskin, D. R., Michel, M. C., Sun, F., Guan, Z. & Morrow, J. D. The effect of elective sham dose escalation on the placebo response during an antimuscarinic trial for overactive bladder symptoms. J. Urol. 187, 1721–1726 (2012).

    Article  PubMed  Google Scholar 

  41. Mallinckrodt, C. et al. A case study comparing a randomized withdrawal trial and a double-blind long-term trial for assessing the long-term efficacy of an antidepressant. Pharm. Stat. 6, 9–22 (2007).

    Article  PubMed  Google Scholar 

  42. Suchman, A. L. & Ader, R. Classic conditioning and placebo effects in crossover studies. Clin. Pharmacol. Ther. 52, 372–377 (1992).

    Article  CAS  PubMed  Google Scholar 

  43. Hrobjartsson, A. & Boutron, I. Blinding in randomized clinical trials: imposed impartiality. Clin. Pharmacol. Ther. 90, 732–736 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Moncrieff, J., Wessely, S. & Hardy, R. Active placebos versus antidepressants for depression. Cochrane Database Syst. Rev. 2004, CD003012 (2004).

    PubMed Central  Google Scholar 

  45. Rief, W. & Glombiewski, J. A. The hidden effects of blinded, placebo controlled randomized trials: an experimental investigation. Pain 153, 2473–2477 (2012).

    Article  PubMed  Google Scholar 

  46. Toth, C. et al. An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. Pain 153, 2073–2082 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. de la Fuente-Fernandez, R. The powerful pre-treatment effect: placebo responses in restless legs syndrome trials. Eur. J. Neurol. 19, 1305–1310 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Tedeschini, E., Fava, M., Goodness, T. M. & Papakostas, G. I. Relationship between probability of receiving placebo and probability of prematurely discontinuing treatment in double-blind, randomized clinical trials for MDD: a meta-analysis. Eur. Neuropsychopharmacol. 20, 562–567 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Zelen, M. A new design for randomized clinical trials. N. Engl. J. Med. 300, 1242–1245 (1979).

    Article  CAS  PubMed  Google Scholar 

  50. Kirsch, I. Are drug and placebo effects in depression additive? Biol. Psychiatry 47, 733–735 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Muthen, B. & Brown, H. C. Estimating drug effects in the presence of placebo response: causal inference using growth mixture modeling. Stat. Med. 28, 3363–3385 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Dworkin, R. H. et al. Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations. Pain 153, 1148–1158 (2012).

    Article  CAS  PubMed  Google Scholar 

  53. US Food and Drug Administration (FDA). Guidance for Industry: E 10 Choice of control group and related issues in clinical trials. FDA website [online], (2001).

  54. Mulla, S. M., Scott, I. A., Jackevicius, C. A., You, J. J. & Guyatt, G. H. How to use a noninferiority trial: users' guides to the medical literature. JAMA 308, 2605–2611 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Woods, S. W., Gueorguieva, R. V., Baker, C. B. & Makuch, R. W. Control group bias in randomized atypical antipsychotic medication trials for schizophrenia. Arch. Gen. Psychiatry 62, 961–970 (2005).

    Article  PubMed  Google Scholar 

  56. Estellat, C. & Ravaud, P. Lack of head-to-head trials and fair control arms: randomized controlled trials of biologic treatment for rheumatoid arthritis. Arch. Intern. Med. 172, 237–244 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Huitfeldt, B., Hummel, J. & the European Federation of Statisticians in the Pharmaceutical Industry (EFSPI). The draft FDA guideline on non-inferiority clinical trials: a critical review from European pharmaceutical industry statisticians. Pharm. Stat. 10, 414–419 (2011).

    Article  PubMed  Google Scholar 

  58. Leon, A. C. Comparative effectiveness clinical trials in psychiatry: superiority, noninferiority, and the role of active comparators. J. Clin. Psychiatry 72, 1344–1349 (2011).

    Article  PubMed  Google Scholar 

  59. Rief, W. et al. Meta-analysis of the placebo response in antidepressant trials. J. Affect. Disord. 118, 1–8 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Hrobjartsson, A. & Gotzsche, P. C. Placebo interventions for all clinical conditions. Cochrane Database Syst. Rev. 2010, CD003974 (2010).

    PubMed Central  Google Scholar 

  61. Kirsch, I. et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 5, e45 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Nijs, J. et al. Recruitment bias in chronic pain research: whiplash as a model. Clin. Rheumatol. 30, 1481–1489 (2011).

    Article  PubMed  Google Scholar 

  63. Kobak, K. A., Kane, J. M., Thase, M. E. & Nierenberg, A. A. Why do clinical trials fail? The problem of measurement error in clinical trials: time to test new paradigms? J. Clin. Psychopharmacol. 27, 1–5 (2007).

    Article  PubMed  Google Scholar 

  64. Pressman, A., Avins, A. L., Neuhaus, J., Ackerson, L. & Rudd, P. Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST). Contemp. Clin. Trials 33, 492–498 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Boehmer, J. & Yong, P. How well does blinding work in randomized controlled trials?: a counterpoint. Clin. Pharmacol. Ther. 85, 463–465 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Cepeda, M. S., Berlin, J. A., Gao, C. Y., Wiegand, F. & Wada, D. R. Placebo response changes depending on the neuropathic pain syndrome: results of a systematic review and meta-analysis. Pain Med. 13, 575–595 (2012).

    Article  PubMed  Google Scholar 

  67. Enck, P., Klosterhalfen, S. & Zipfel, S. Novel study designs to investigate the placebo response. BMC Med. Res. Methodol. 11, 90 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Colloca, L., Lopiano, L., Lanotte, M. & Benedetti, F. Overt versus covert treatment for pain, anxiety, and Parkinson's disease. Lancet Neurol. 3, 679–684 (2004).

    Article  PubMed  Google Scholar 

  69. Enck, P., Grundy, D. & Klosterhalfen, S. A novel placebo-controlled clinical study design without ethical concerns — the free choice paradigm. Med. Hypotheses 79, 880–882 (2012).

    Article  PubMed  Google Scholar 

  70. O'Neil, C. C. & Miller, F. G. When scientists deceive: applying the federal regulations. J. Law Med. Eth. 37, 344–350 (2009).

    Article  Google Scholar 

  71. Fässler, M., Meissner, K., Schneider, A. & Linde, K. Frequency and circumstances of placebo use in clinical practice — a systematic review of empirical studies. BMC Med. 8, 15 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Miller, F. G. & Colloca, L. The placebo phenomenon and medical ethics: rethinking the relationship between informed consent and risk–benefit assessment. Theor. Med. Bioeth. 32, 29–43 (2011).

    Article  Google Scholar 

  73. Kaptchuk, T. J. et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS ONE 5, e15591 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Juergens, M. C., Seekatz, B., Moosdorf, R. G., Petrie, K. J. & Rief, W. Illness beliefs before cardiac surgery predict disability, quality of life, and depression 3 months later. J. Psychosom. Res. 68, 553–560 (2010).

    Article  PubMed  Google Scholar 

  75. Petrie, K. J., Cameron, L. D., Ellis, C. J., Buick, D. & Weinman, J. Changing illness perceptions after myocardial infarction: an early intervention randomized controlled trial. Psychosom. Med. 64, 580–586 (2002).

    Article  PubMed  Google Scholar 

  76. Barefoot, J. C. et al. Recovery expectations and long-term prognosis of patients with coronary heart disease. Arch. Intern. Med. 171, 929–935 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Judge, A. et al. Pre-operative expectation predicts 12-month post-operative outcome among patients undergoing primary total hip replacement in European orthopaedic centres. Osteoarthritis Cartilage 19, 659–667 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Mercado, R. et al. Expectation and the placebo effect in Parkinson's disease patients with subthalamic nucleus deep brain stimulation. Mov. Disord. 21, 1457–1461 (2006).

    Article  PubMed  Google Scholar 

  79. Chen, J. A. et al. Association between patient beliefs regarding assigned treatment and clinical response: reanalysis of data from the Hypericum Depression Trial Study Group. J. Clin. Psychiat. 72, 1669–1676 (2011).

    Article  Google Scholar 

  80. Bodenheimer, T. The future of primary care: transforming practice. N. Engl. J. Med. 359, 2086–2089 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Acosta, J. I., Thiel, K. J., Sanabria, F., Browning, J. R. & Neisewander, J. L. Effect of schedule of reinforcement on cue-elicited reinstatement of cocaine-seeking behavior. Behav. Pharmacol. 19, 129–136 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Ader, R. et al. Conditioned pharmacotherapeutic effects: a preliminary study. Psychosom. Med. 72, 192–197 (2010).

    Article  PubMed  Google Scholar 

  83. Sandler, A. D., Glesne, C. E. & Bodfish, J. W. Conditioned placebo dose reduction: a new treatment in attention-deficit hyperactivity disorder? J. Dev. Behav. Pediatr. 31, 369–375 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Ader, R. in The Placebo Effect: An Interdisciplinary Exploration (ed. Harrington, A.) 138–165 (Harvard Univ. Press, 1997).

    Google Scholar 

  85. Hadamitzky, M., Engler, H. & Schedlowski, M. Learned immunosuppression: extinction, renewal, and the challenge of reconsolidation. J. Neuroimmune Pharmacol. 13 Jul 2012 (doi:10.1007/s11481-012-9388-6).

    Article  PubMed  Google Scholar 

  86. Koudriavtseva, T., Onesti, E., Pestalozza, I. F., Sperduti, I. & Jandolo, B. The importance of physician–patient relationship for improvement of adherence to long-term therapy: data of survey in a cohort of multiple sclerosis patients with mild and moderate disability. Neurol. Sci. 33, 575–584 (2012).

    Article  PubMed  Google Scholar 

  87. Schneider, R. & Kuhl, J. Placebo forte: ways to maximize unspecific treatment effects. Med. Hypotheses 78, 744–751 (2012).

    Article  PubMed  Google Scholar 

  88. Waber, R. L., Shiv, B., Carmon, Z. & Ariely, D. Commercial features of placebo and therapeutic efficacy. JAMA 299, 1016–1017 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. Linde, K. et al. Acupuncture for patients with migraine: a randomized controlled trial. JAMA 293, 2118–2125 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Ober, K. et al. Plasma noradrenaline and state anxiety levels predict placebo response in learned immunosuppression. Clin. Pharmacol. Ther. 91, 220–226 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Wager, T. D., Atlas, L. Y., Leotti, L. A. & Rilling, J. K. Predicting individual differences in placebo analgesia: contributions of brain activity during anticipation and pain experience. J. Neurosci. 31, 439–452 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Stein, N., Sprenger, C., Scholz, J., Wiech, K. & Bingel, U. White matter integrity of the descending pain modulatory system is associated with inter-individual differences in placebo analgesia. Pain 153, 2210–2217 (2012).

    Article  PubMed  Google Scholar 

  93. Benedetti, F. et al. Loss of expectation-related mechanisms in Alzheimer's disease makes analgesic therapies less effective. Pain 121, 133–144 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Baeken, C., Vanderhasselt, M. A. & De Raedt, R. Baseline 'state anxiety' influences HPA-axis sensitivity to one sham-controlled HF-rTMS session applied to the right dorsolateral prefrontal cortex. Psychoneuroendocrinology 36, 60–67 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Lyby, P. S., Aslaksen, P. M. & Flaten, M. A. Variability in placebo analgesia and the role of fear of pain — an ERP study. Pain 152, 2405–2412 (2011).

    Article  PubMed  Google Scholar 

  96. Flaten, M. A., Aslaksen, P. M., Lyby, P. S. & Bjorkedal, E. The relation of emotions to placebo responses. Phil. Trans. R. Soc. B 366, 1818–1827 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Linde, K. et al. The impact of patient expectations on outcomes in four randomized controlled trials of acupuncture in patients with chronic pain. Pain 128, 264–271 (2007).

    Article  PubMed  Google Scholar 

  98. Flaten, M. A., Aslaksen, P. M., Finset, A., Simonsen, T. & Johansen, O. Cognitive and emotional factors in placebo analgesia. J. Psychosom. Res. 61, 81–89 (2006).

    Article  PubMed  Google Scholar 

  99. Geers, A. L., Helfer, S. G., Kosbab, K., Weiland, P. E. & Landry, S. J. Reconsidering the role of personality in placebo effects: dispositional optimism, situational expectations, and the placebo response. J. Psychosom. Res. 58, 121–127 (2005).

    Article  PubMed  Google Scholar 

  100. Morton, D. L., Watson, A., El-Deredy, W. & Jones, A. K. Reproducibility of placebo analgesia: effect of dispositional optimism. Pain 146, 194–198 (2009).

    Article  PubMed  Google Scholar 

  101. Geers, A. L., Wellman, J. A., Fowler, S. L., Helfer, S. G. & France, C. R. Dispositional optimism predicts placebo analgesia. J. Pain. 11, 1165–1171 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  102. De Pascalis, V., Chiaradia, C. & Carotenuto, E. The contribution of suggestibility and expectation to placebo analgesia phenomenon in an experimental setting. Pain 96, 393–402 (2002).

    Article  PubMed  Google Scholar 

  103. Reynaert, C., Janne, P., Vause, M., Zdanowicz, N. & Lejeune, D. Clinical trials of antidepressants: the hidden face: where locus of control appears to play a key role in depression outcome. Psychopharmacology 119, 449–454 (1995).

    Article  CAS  PubMed  Google Scholar 

  104. Moerman, D. E. Cultural variations in the placebo effect: ulcers, anxiety, and blood pressure. Med. Anthropol. Quarterly 14, 51–72 (2000).

    Article  CAS  Google Scholar 

  105. Schneider, A. et al. Acupuncture treatment in irritable bowel syndrome. Gut 55, 649–654 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lindstedt, F. et al. Conditioned pain modulation is associated with common polymorphisms in the serotonin transporter gene. PLoS ONE 6, e18252 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Leuchter, A. F., McCracken, J. T., Hunter, A. M., Cook, I. A. & Alpert, J. E. Monoamine oxidase A and catechol-O-methyltransferase functional polymorphisms and the placebo response in major depressive disorder. J. Clin. Psychopharmacol. 29, 372–377 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Kaptchuk, T. J. et al. Do “placebo responders” exist? Contemp. Clin. Trials. 29, 587–595 (2008).

    Article  PubMed  Google Scholar 

  109. Whalley, B., Hyland, M. E. & Kirsch, I. Consistency of the placebo effect. J. Psychosom. Res. 64, 537–541 (2008).

    Article  PubMed  Google Scholar 

  110. Caponigro, G. & Sellers, W. R. Advances in the preclinical testing of cancer therapeutic hypotheses. Nature Rev. Drug Discov. 10, 179–187 (2011).

    Article  CAS  Google Scholar 

  111. Beckman, R. A., Clark, J. & Chen, C. Integrating predictive biomarkers and classifiers into oncology clinical development programmes. Nature Rev. Drug Discov. 10, 735–748 (2011).

    Article  CAS  Google Scholar 

  112. Colloca, L., Sigaudo, M. & Benedetti, F. The role of learning in nocebo and placebo effects. Pain 136, 211–218 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Iovieno, N. & Papakostas, G. I. Does the presence of an open-label antidepressant treatment period influence study outcome in clinical trials examining augmentation/combination strategies in treatment partial responders/nonresponders with major depressive disorder? J. Clin. Psychiatry 73, 676–683 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Wechsler, M. E. et al. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N. Engl. J. Med. 365, 119–126 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Finniss, D. G., Kaptchuk, T. J., Miller, F. & Benedetti, F. Biological, clinical, and ethical advances of placebo effects. Lancet 375, 686–695 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  116. McRae, C. et al. Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Arch. Gen. Psychiatry 61, 412–420 (2004).

    Article  PubMed  Google Scholar 

  117. Moseley, J. B. et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N. Engl. J. Med. 347, 81–88 (2002).

    Article  PubMed  Google Scholar 

  118. Quessy, S. N. & Rowbotham, M. C. Placebo response in neuropathic pain trials. Pain 138, 479–483 (2008).

    Article  PubMed  Google Scholar 

  119. Khan, A. Redding, N. & Brown, W. A. The persistence of the placebo response in antidepressant clinical trials. J. Psychiatr. Res. 42, 791–796 (2008).

    Article  PubMed  Google Scholar 

  120. Colloca, L. & Benedetti, F. Nocebo hyperalgesia: how anxiety is turned into pain. Curr. Opin. Anaesthesiol. 20, 435–439 (2007).

    Article  PubMed  Google Scholar 

  121. Colloca, L. & Finniss, D. Nocebo effects, patient–clinician communication, and therapeutic outcomes. JAMA 307, 567–568 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Sullivan, R., Behncke, I. & Purushotham, A. Why do we love medicines so much? An evolutionary perspective on the human love of pills, potions and placebo. EMBO Rep. 11, 572–578 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Volkow, N. D. et al. Expectation enhances the regional brain metabolic and the reinforcing effects of stimulants in cocaine abusers. J. Neurosci. 23, 11461–11468 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Benedetti, F., Amanzio, M., Baldi, S., Casadio, C. & Maggi, G. Inducing placebo respiratory depressant responses in humans via opioid receptors. Eur. J. Neurosci. 11, 625–631 (1999).

    Article  CAS  PubMed  Google Scholar 

  125. Isenberg, S. A., Lehrer, P. M. & Hochron, S. The effects of suggestion and emotional arousal on pulmonary function in asthma — a review and a hypothesis regarding vagal mediation. Psychosom. Med. 54, 192–216 (1992).

    Article  CAS  PubMed  Google Scholar 

  126. Pollo, A., Vighetti, S., Rainero, I. & Benedetti, F. Placebo analgesia and the heart. Pain 102, 125–133 (2003).

    Article  PubMed  Google Scholar 

  127. Ronel, J. et al. Effects of verbal suggestion on coronary arteries: results of a randomized controlled experimental investigation during coronary angiography. Am. Heart J. 162, 507–511 (2011).

    Article  PubMed  Google Scholar 

  128. Amigo, I., Cuesta, V., Fernandez, A. & Gonzalez, A. The effect of verbal instructions on blood pressure measurement. J. Hypertens. 11, 293–296 (1993).

    Article  CAS  PubMed  Google Scholar 

  129. Lanotte, M. et al. Expectation enhances autonomic responses to stimulation of the human subthalamic limbic region. Brain Behav. Immun. 19, 500–509 (2005).

    Article  PubMed  Google Scholar 

  130. Elsenbruch, S. et al. Neural mechanisms mediating the effects of expectation in visceral placebo analgesia: an fMRI study in healthy placebo responders and non-responders. Pain 153, 382–390 (2012).

    Article  PubMed  Google Scholar 

  131. Price, D. D., Craggs, J., Verne, G. N., Perlstein, W. M. & Robinson, M. E. Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients. Pain 127, 63–72 (2007).

    Article  PubMed  Google Scholar 

  132. Meissner, K. Effects of placebo interventions on gastric motility and general autonomic activity. J. Psychosom. Res. 66, 391–398 (2009).

    Article  PubMed  Google Scholar 

  133. Scott, D. J. et al. Individual differences in reward responding explain placebo-induced expectations and effects. Neuron 55, 325–336 (2007).

    Article  CAS  PubMed  Google Scholar 

  134. Scott, D. J. et al. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch. Gen. Psychiatry 65, 220–231 (2008).

    Article  PubMed  Google Scholar 

  135. Hall, K. T. et al. Catechol-O-methyltransferase Val158Met polymorphism predicts placebo effect in irritable bowel syndrome. PLoS ONE 7, e48135 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Benedetti, F. et al. Electrophysiological properties of thalamic, subthalamic and nigral neurons during the anti-parkinsonian placebo response. J. Physiol. 587, 3869–3883 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Potkin, S. et al. Placebo response trajectories in short-term and long-term antipsychotic trials in schizophrenia. Schizophr. Res. 132, 108–113 (2011).

    Article  PubMed  Google Scholar 

  138. Lee, S., Walker, J. R., Jakul, L. & Sexton, K. Does elimination of placebo responders in a placebo run-in increase the treatment effect in randomized clinical trials? A meta-analytic evaluation. Depress. Anxiety 19, 10–19 (2004).

    Article  PubMed  Google Scholar 

  139. Madsen, L. G. & Bytzer, P. Single subject trials as a research instrument in gastrointestinal pharmacology. Aliment. Pharmacol. Ther. 16, 189–196 (2002).

    Article  CAS  PubMed  Google Scholar 

  140. Ivanova, A. & Tamura, R. N. A two-way enriched clinical trial design: combining advantages of placebo lead-in and randomized withdrawal. Stat. Methods Med. Res. 4 Dec 2011 (doi:10.1177/0962280211431023).

    Article  PubMed  Google Scholar 

  141. King, M. et al. Conceptual framework and systematic review of the effects of participants' and professionals' preferences in randomised controlled trials. Health Technol. Assess. 9, 1–186 (2005).

    Article  CAS  PubMed  Google Scholar 

  142. De Allegri, M. et al. Step-wedge cluster-randomised community-based trials: an application to the study of the impact of community health insurance. Health Res. Policy Syst. 6, 10 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Weijer, C. et al. The Ottawa statement on the ethical design and conduct of cluster randomized trials. PLoS Med. 9, e1001346 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Kaptchuk, T. J. et al. Do “placebo responders” exist? Contemp. Clin. Trials. 29, 587–595 (2008).

    Article  PubMed  Google Scholar 

  145. Mondaini, N. et al. Finasteride 5 mg and sexual side effects: how many of these are related to a nocebo phenomenon? J. Sex. Med. 4, 1708–1712 (2007).

    Article  PubMed  Google Scholar 

  146. Petrie, K. J. et al. Effect of providing information about normal test results on patients' reassurance: randomised controlled trial. BMJ 334, 352–353 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Colloca, L. & Benedetti, F. How prior experience shapes placebo analgesia. Pain 124, 126–133 (2006).

    Article  PubMed  Google Scholar 

  148. Eikelboom, R. & Stewart, J. Conditioning of drug-induced physiological responses. Psych. Rev. 89, 507–528 (1982).

    Article  CAS  Google Scholar 

  149. Barsky, A. J., Saintfort, R., Rogers, M. P. & Borus, J. F. Nonspecific medication side effects and the nocebo phenomenon. JAMA 287, 622–626 (2002).

    Article  PubMed  Google Scholar 

  150. Preston, R. A., Materson, B. J., Reda, D. J. & Williams, D. W. Placebo-associated blood pressure response and adverse effects in the treatment of hypertension. Arch. Intern. Med. 160, 1449–1454 (2000).

    Article  CAS  PubMed  Google Scholar 

  151. Rief, W., Avorn, J. & Barsky, A. J. Medication-attributed adverse effects in placebo groups. Implications for assessment of adverse effects. Arch. Intern. Med. 166, 155–160 (2006).

    Article  PubMed  Google Scholar 

  152. Rief, W. et al. Differences in adverse effect reporting in placebo groups in SSRI and tricyclic antidepressant trials. A systematic review and meta-analysis. Drug Safety 32, 1041–1056 (2009).

    Article  CAS  PubMed  Google Scholar 

  153. de la Cruz, M., Hui, D., Parsons, H. A. & Bruera, E. Placebo and nocebo effects in randomized double-blind clinical trials of agents for the therapy for fatigue in patients with advanced cancer. Cancer 116, 766–774 (2010).

    Article  PubMed  Google Scholar 

  154. Häuser, W., Bartram, C., Bartram-Wunn, E. & Tolle, T. Adverse events attributable to nocebo in randomized controlled drug trials in fibromyalgia syndrome and painful diabetic peripheral neuropathy: systematic review. Clin. J. Pain 28, 437–451 (2012).

    Article  PubMed  Google Scholar 

  155. Amanzio, M., Corazzini, L. L., Vase, L. & Benedetti, F. A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain 146, 261–269 (2009).

    Article  CAS  PubMed  Google Scholar 

  156. Papadopoulos, D. & Mitsikostas, D. D. Nocebo effects in multiple sclerosis trials: a meta-analysis. Mult. Scler. 16, 816–828 (2010).

    Article  CAS  PubMed  Google Scholar 

  157. Wise, R. A. et al. Randomized trial of the effect of drug presentation on asthma outcomes: the American Lung Association Asthma Clinical Research Centers. J. Allergy Clin. Immunol. 124, 436–444.e8 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Koyama, T., McHaffie, J. G., Laurienti, P. J. & Coghill, R. C. The subjective experience of pain: where expectations become reality. Proc. Natl Acad. Sci. USA 102, 12950–12955 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Keltner, J. R. et al. Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study. J. Neurosci. 26, 4437–4443 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Craig, K. D. & Prkachin, K. M. Social modeling influences on sensory decision theory and psychophysiological indexes of pain. J. Pers. Soc. Psychol. 36, 805–815 (1978).

    Article  CAS  PubMed  Google Scholar 

  161. Nestoriuc, Y., Orav, E. J., Liang, M. H., Horne, R. & Barsky, A. J. Prediction of nonspecific side effects in rheumatoid arthritis patients by beliefs about medicines. Arthritis Care Res. 62, 791–799 (2010).

    Article  Google Scholar 

  162. Petrie, K. J. et al. Worries about modernity predict symptom complaints after environmental pesticide spraying. Psychosom. Med. 67, 778–782 (2005).

    Article  PubMed  Google Scholar 

  163. Jackevicius, C. A., Mamdani, M. & Tu, J. V. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 288, 462–467 (2002).

    Article  PubMed  Google Scholar 

  164. Colagiuri, B., McGuinness, K., Boakes, R. A. & Butow, P. N. Warning about side effects can increase their occurrence: an experimental model using placebo treatment for sleep difficulty. J. Psychopharmacol. 26, 1540–1547 (2012).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

All authors are participants of a collaborative research group dedicated to studying placebo and nocebo mechanisms across different physiological systems in health and disease. This work was supported by grants from the German Research Foundation (DFG) for the Research Unit FOR 1328 (BI 89/2-1; EN 50/30-1; RI 574/21-1; RI 574-22-1; SCHE 341/17-1), the Volkswagen Foundation Germany (P.E.: I/83 805; M.S.: I/83 806) and the German Federal Ministry of Education and Research (U.B.: 01GQ0808).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paul Enck.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Paul Enck's homepage

Ulrike Bingel's homepage

Manfred Schedlowski's homepage

Winfried Rief's homepage

Glossary

Active placebo

A substance or treatment that mimics the side effects of the active compound under investigation and is thus, by definition, not an inert substance. In clinical trials, active placebos are administered to avoid un-blinding owing to different side-effect profiles of drugs and placebo treatments.

Assay sensitivity

The ability of a clinical trial to differentiate between an effective treatment (for example, a drug) and a less effective or ineffective treatment (for example, placebo).

CER trial

A comparative effectiveness research (CER) trial is performed to analyse the efficacy of a novel pharmacological agent or treatment in comparison with standard treatments or approved drugs. Patients are therefore randomly allocated to receive the treatment under investigation or one or more standard treatments.

Declaration of Helsinki

A statement, developed by the World Medical Association (WMA), of ethical principles for medical research involving human participants, identifiable human material and data.

Health locus of control

The extent to which individuals believe that they can control events that affect their personal health.

Open/hidden study

An experimental approach undertaken to separate the effects of the psychosocial context (placebo) from the pharmacodynamic effects of a drug under investigation. The pharmacological agent is administered either in an open condition (by a physician in a visible way) or in a hidden condition, in which the patient is unaware of the timing of the administration of the medication (for example, the drug is administered using computer-controlled infusion).

Open-label

A method of application in which both the patients (or participants) and the investigators know which pharmacological agent or treatment is being administered. This design contrasts the single- or double-blind study designs.

Patient-reported outcomes

(PROs). A method of measuring treatment efficacy via the states of symptom severity and health from the patient's perspective, instead of physician's reports or biomarkers of clinical outcome. PROs are typically analysed via questionnaires or interviews, providing insight into how patients perceive the impact of a treatment on their health and quality of life.

Placebo

Latin term for “I shall please”. Used to indicate sham treatments or inert substances such as sugar pills or saline infusions.

Placebo effects

Defined as any improvements in a symptom or physiological condition of individuals following a placebo treatment. There are different mechanisms underlying this phenomenon, including spontaneous remission, regression to the mean, natural course of a disease, biases and placebo responses.

Placebo responses

The outcomes caused by a placebo manipulation. The placebo response reflects the neurobiological and psychophysiological response of an individual to an inert substance or sham treatment and is mediated by various factors that make up the treatment context. Importantly, placebo responses are not restricted to placebo treatments and can also modulate the outcome of any active treatment.

Randomized double-blind placebo-controlled trials

(RCTs). The most commonly used clinical trial design for testing the efficacy of a treatment within a patient population. Patients are randomly allocated to a treatment or placebo group. Patients and investigators are blinded to group allocation. The design aims to control for confounding factors such as suggestion, imagination and biases for the patient and investigator, as well as spontaneous fluctuation of diseases and symptoms.

Regression to the mean

A statistical phenomenon; individuals tend to have extreme values in symptom severity or physiological parameters when enrolled into a clinical trial. These values tend to be lower and closer to the average at subsequent assessments, because they are more likely to change in the direction of the mean score, instead of developing even more extreme scores. This phenomenon in part explains the improvement observed in placebo groups in clinical trials.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Enck, P., Bingel, U., Schedlowski, M. et al. The placebo response in medicine: minimize, maximize or personalize?. Nat Rev Drug Discov 12, 191–204 (2013). https://doi.org/10.1038/nrd3923

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd3923

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research