Opinion | Published:

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

Nature Reviews Drug Discovery volume 12, pages 191204 (2013) | Download Citation

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

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

  2. 2.

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

  3. 3.

    & Utilizing placebo mechanisms for dose reduction in pharmacotherapy. Trends Pharmacol. Sci. 33, 165–172 (2012).

  4. 4.

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

  5. 5.

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

  6. 6.

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

  7. 7.

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

  8. 8.

    Descending control of pain. Prog. Neurobiol. 66, 355–474 (2002).

  9. 9.

    , , & Direct evidence for spinal cord involvement in placebo analgesia. Science 326, 404 (2009).

  10. 10.

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

  11. 11.

    , , & Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nature Med. 17, 1228–1230 (2011).

  12. 12.

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

  13. 13.

    , & Placebo effects on human μ-opioid activity during pain. Proc. Natl Acad. Sci. USA 104, 11056–11061 (2007).

  14. 14.

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

  15. 15.

    , & The mechanism of placebo analgesia. Lancet 2, 654–657 (1978).

  16. 16.

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

  17. 17.

    et al. Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease. Science 293, 1164–1166 (2001).

  18. 18.

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

  19. 19.

    , , , & Changes in brain function of depressed subjects during treatment with placebo. Am. J. Psychiatry 159, 122–129 (2002).

  20. 20.

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

  21. 21.

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

  22. 22.

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

  23. 23.

    & Behaviorally conditioned immunosuppression. Psychosom. Med. 37, 333–340 (1975).

  24. 24.

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

  25. 25.

    , , , & Behavioral conditioning of antihistamine effects in patients with allergic rhinitis. Psychother. Psychosom. 77, 227–234 (2008).

  26. 26.

    & The learned immune response: Pavlov and beyond. Brain Behav. Immun. 24, 176–185 (2010).

  27. 27.

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

  28. 28.

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

  29. 29.

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

  30. 30.

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

  31. 31.

    , , & Mechanisms involved in placebo and nocebo responses and implications for drug trials. Clin. Pharmacol. Ther. 90, 722–726 (2011).

  32. 32.

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

  33. 33.

    , , , & Unbalanced randomization influences placebo response: scientific versus ethical issues around the use of placebo in migraine trials. Cephalalgia 19, 699–700 (1999).

  34. 34.

    & 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).

  35. 35.

    , , & Signal detection and placebo response in schizophrenia: parallels with depression. Psychopharmacol. Bull. 43, 53–72 (2010).

  36. 36.

    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).

  37. 37.

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

  38. 38.

    , & Does study design influence outcome? The effects of placebo control and treatment duration in antidepressant trials. Psychother. Psychosom. 78, 172–181 (2009).

  39. 39.

    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).

  40. 40.

    , , , & 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).

  41. 41.

    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).

  42. 42.

    & Classic conditioning and placebo effects in crossover studies. Clin. Pharmacol. Ther. 52, 372–377 (1992).

  43. 43.

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

  44. 44.

    , & Active placebos versus antidepressants for depression. Cochrane Database Syst. Rev. 2004, CD003012 (2004).

  45. 45.

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

  46. 46.

    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).

  47. 47.

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

  48. 48.

    , , & 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).

  49. 49.

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

  50. 50.

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

  51. 51.

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

  52. 52.

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

  53. 53.

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

  54. 54.

    , , , & How to use a noninferiority trial: users' guides to the medical literature. JAMA 308, 2605–2611 (2012).

  55. 55.

    , , & Control group bias in randomized atypical antipsychotic medication trials for schizophrenia. Arch. Gen. Psychiatry 62, 961–970 (2005).

  56. 56.

    & 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).

  57. 57.

    , & 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).

  58. 58.

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

  59. 59.

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

  60. 60.

    & Placebo interventions for all clinical conditions. Cochrane Database Syst. Rev. 2010, CD003974 (2010).

  61. 61.

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

  62. 62.

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

  63. 63.

    , , & 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).

  64. 64.

    , , , & Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST). Contemp. Clin. Trials 33, 492–498 (2012).

  65. 65.

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

  66. 66.

    , , , & Placebo response changes depending on the neuropathic pain syndrome: results of a systematic review and meta-analysis. Pain Med. 13, 575–595 (2012).

  67. 67.

    , & Novel study designs to investigate the placebo response. BMC Med. Res. Methodol. 11, 90 (2011).

  68. 68.

    , , & Overt versus covert treatment for pain, anxiety, and Parkinson's disease. Lancet Neurol. 3, 679–684 (2004).

  69. 69.

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

  70. 70.

    & When scientists deceive: applying the federal regulations. J. Law Med. Eth. 37, 344–350 (2009).

  71. 71.

    , , & Frequency and circumstances of placebo use in clinical practice — a systematic review of empirical studies. BMC Med. 8, 15 (2010).

  72. 72.

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

  73. 73.

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

  74. 74.

    , , , & Illness beliefs before cardiac surgery predict disability, quality of life, and depression 3 months later. J. Psychosom. Res. 68, 553–560 (2010).

  75. 75.

    , , , & Changing illness perceptions after myocardial infarction: an early intervention randomized controlled trial. Psychosom. Med. 64, 580–586 (2002).

  76. 76.

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

  77. 77.

    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).

  78. 78.

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

  79. 79.

    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).

  80. 80.

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

  81. 81.

    , , , & Effect of schedule of reinforcement on cue-elicited reinstatement of cocaine-seeking behavior. Behav. Pharmacol. 19, 129–136 (2008).

  82. 82.

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

  83. 83.

    , & Conditioned placebo dose reduction: a new treatment in attention-deficit hyperactivity disorder? J. Dev. Behav. Pediatr. 31, 369–375 (2010).

  84. 84.

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

  85. 85.

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

  86. 86.

    , , , & 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).

  87. 87.

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

  88. 88.

    , , & Commercial features of placebo and therapeutic efficacy. JAMA 299, 1016–1017 (2008).

  89. 89.

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

  90. 90.

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

  91. 91.

    , , & Predicting individual differences in placebo analgesia: contributions of brain activity during anticipation and pain experience. J. Neurosci. 31, 439–452 (2011).

  92. 92.

    , , , & White matter integrity of the descending pain modulatory system is associated with inter-individual differences in placebo analgesia. Pain 153, 2210–2217 (2012).

  93. 93.

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

  94. 94.

    , & 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).

  95. 95.

    , & Variability in placebo analgesia and the role of fear of pain — an ERP study. Pain 152, 2405–2412 (2011).

  96. 96.

    , , & The relation of emotions to placebo responses. Phil. Trans. R. Soc. B 366, 1818–1827 (2011).

  97. 97.

    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).

  98. 98.

    , , , & Cognitive and emotional factors in placebo analgesia. J. Psychosom. Res. 61, 81–89 (2006).

  99. 99.

    , , , & Reconsidering the role of personality in placebo effects: dispositional optimism, situational expectations, and the placebo response. J. Psychosom. Res. 58, 121–127 (2005).

  100. 100.

    , , & Reproducibility of placebo analgesia: effect of dispositional optimism. Pain 146, 194–198 (2009).

  101. 101.

    , , , & Dispositional optimism predicts placebo analgesia. J. Pain. 11, 1165–1171 (2010).

  102. 102.

    , & The contribution of suggestibility and expectation to placebo analgesia phenomenon in an experimental setting. Pain 96, 393–402 (2002).

  103. 103.

    , , , & 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).

  104. 104.

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

  105. 105.

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

  106. 106.

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

  107. 107.

    , , , & Monoamine oxidase A and catechol-O-methyltransferase functional polymorphisms and the placebo response in major depressive disorder. J. Clin. Psychopharmacol. 29, 372–377 (2009).

  108. 108.

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

  109. 109.

    , & Consistency of the placebo effect. J. Psychosom. Res. 64, 537–541 (2008).

  110. 110.

    & Advances in the preclinical testing of cancer therapeutic hypotheses. Nature Rev. Drug Discov. 10, 179–187 (2011).

  111. 111.

    , & Integrating predictive biomarkers and classifiers into oncology clinical development programmes. Nature Rev. Drug Discov. 10, 735–748 (2011).

  112. 112.

    , & The role of learning in nocebo and placebo effects. Pain 136, 211–218 (2008).

  113. 113.

    & 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).

  114. 114.

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

  115. 115.

    , , & Biological, clinical, and ethical advances of placebo effects. Lancet 375, 686–695 (2010).

  116. 116.

    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).

  117. 117.

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

  118. 118.

    & Placebo response in neuropathic pain trials. Pain 138, 479–483 (2008).

  119. 119.

    & The persistence of the placebo response in antidepressant clinical trials. J. Psychiatr. Res. 42, 791–796 (2008).

  120. 120.

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

  121. 121.

    & Nocebo effects, patient–clinician communication, and therapeutic outcomes. JAMA 307, 567–568 (2012).

  122. 122.

    , & 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).

  123. 123.

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

  124. 124.

    , , , & Inducing placebo respiratory depressant responses in humans via opioid receptors. Eur. J. Neurosci. 11, 625–631 (1999).

  125. 125.

    , & 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).

  126. 126.

    , , & Placebo analgesia and the heart. Pain 102, 125–133 (2003).

  127. 127.

    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).

  128. 128.

    , , & The effect of verbal instructions on blood pressure measurement. J. Hypertens. 11, 293–296 (1993).

  129. 129.

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

  130. 130.

    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).

  131. 131.

    , , , & Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients. Pain 127, 63–72 (2007).

  132. 132.

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

  133. 133.

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

  134. 134.

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

  135. 135.

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

  136. 136.

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

  137. 137.

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

  138. 138.

    , , & 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).

  139. 139.

    & Single subject trials as a research instrument in gastrointestinal pharmacology. Aliment. Pharmacol. Ther. 16, 189–196 (2002).

  140. 140.

    & 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).

  141. 141.

    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).

  142. 142.

    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).

  143. 143.

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

  144. 144.

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

  145. 145.

    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).

  146. 146.

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

  147. 147.

    & How prior experience shapes placebo analgesia. Pain 124, 126–133 (2006).

  148. 148.

    & Conditioning of drug-induced physiological responses. Psych. Rev. 89, 507–528 (1982).

  149. 149.

    , , & Nonspecific medication side effects and the nocebo phenomenon. JAMA 287, 622–626 (2002).

  150. 150.

    , , & Placebo-associated blood pressure response and adverse effects in the treatment of hypertension. Arch. Intern. Med. 160, 1449–1454 (2000).

  151. 151.

    , & Medication-attributed adverse effects in placebo groups. Implications for assessment of adverse effects. Arch. Intern. Med. 166, 155–160 (2006).

  152. 152.

    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).

  153. 153.

    , , & 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).

  154. 154.

    , , & 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).

  155. 155.

    , , & A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain 146, 261–269 (2009).

  156. 156.

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

  157. 157.

    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).

  158. 158.

    , , & The subjective experience of pain: where expectations become reality. Proc. Natl Acad. Sci. USA 102, 12950–12955 (2005).

  159. 159.

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

  160. 160.

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

  161. 161.

    , , , & Prediction of nonspecific side effects in rheumatoid arthritis patients by beliefs about medicines. Arthritis Care Res. 62, 791–799 (2010).

  162. 162.

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

  163. 163.

    , & Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 288, 462–467 (2002).

  164. 164.

    , , & Warning about side effects can increase their occurrence: an experimental model using placebo treatment for sleep difficulty. J. Psychopharmacol. 26, 1540–1547 (2012).

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

Author notes

    • Paul Enck
    • , Ulrike Bingel
    • , Manfred Schedlowski
    •  & Winfried Rief

    All authors contributed equally to this work.

Affiliations

  1. Paul Enck is at the Department of Internal Medicine VI, University Hospital Tübingen, 72076 Tübingen, Germany.

    • Paul Enck
  2. Ulrike Bingel is at the Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

    • Ulrike Bingel
  3. Manfred Schedlowski is at the Institute of Medical Psychology and Behavioural Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.

    • Manfred Schedlowski
  4. Winfried Rief is at the Division of Clinical Psychology, University of Marburg, 35032 Marburg, Germany.

    • Winfried Rief

Authors

  1. Search for Paul Enck in:

  2. Search for Ulrike Bingel in:

  3. Search for Manfred Schedlowski in:

  4. Search for Winfried Rief in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Paul Enck.

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.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrd3923

Further reading