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Placebos and the Placebo Effect in Drug Trials

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Concepts and Principles of Pharmacology

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 260))

Abstract

In this review, we explored different ways of controlling the placebo effects in clinical trials and described various factors that may increase/decrease the placebo effect in randomized placebo-controlled trials. These factors can be subdivided into four groups, and while not all factors are effective in every study and under all clinical conditions, they show on the whole that – even under the ideal condition of drug therapy, where blinded placebo provision is much easier and warranted than in, e.g., psychotherapy – many factors need to be controlled to ascertain that the goal of the clinical trials, fair assessment of superiority of the drug over placebo in placebo-controlled trials and fair assessment of non-inferiority of the drug compared to another drug in comparator trials, is reached. Ignorance towards the placebo effect, which was common in the past, is no longer acceptable; instead, it should be the goal of all therapeutic trials to minimize the placebo effect in clinical trials, while utilizing and maximizing it in clinical routine.

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References

  • Agid O, Siu CO, Potkin SG, Kapur S, Watsky E, Vanderburg D, Zipursky RB, Remington G (2013) Meta-regression analysis of placebo response in antipsychotic trials, 1970-2010. Am J Psychiatry 170(11):1335–1344

    PubMed  Google Scholar 

  • Aslaksen PM, Myrbakk IN, Hoifodt RS, Flaten MA (2007) The effect of experimenter gender on autonomic and subjective responses to pain stimuli. Pain 129(3):260–268

    PubMed  Google Scholar 

  • Bakalos G, Zintzaras E (2018) Drug discontinuation in studies including a switch from an originator to a biosimilar monoclonal antibody: a systematic literature review. Clin Ther 41(1):155–173

    PubMed  Google Scholar 

  • Beecher HK (1955) The powerful placebo. J Am Med Assoc 159(17):1602–1606

    CAS  PubMed  Google Scholar 

  • Benedetti F (2014) Placebo effects. Oxford University Press, Oxford

    Google Scholar 

  • Benedetti F, Frisaldi E (2014) Creating placebo responders and nonresponders in the laboratory: boons and banes. Pain Manag 4(3):165–167

    PubMed  Google Scholar 

  • Benedetti F, Enck P, Frisaldi E, Schedlowski M (eds) (2014) Placebo, Handbook of experimental pharmacology, vol 225. Springer, Heidelberg

    Google Scholar 

  • Bridge JA, Birmaher B, Iyengar S, Barbe RP, Brent DA (2009) Placebo response in randomized controlled trials of antidepressants for pediatric major depressive disorder. Am J Psychiatry 166(1):42–49

    PubMed  Google Scholar 

  • Burke MJ, Kaptchuk TJ, Pascual-Leone A (2018) Challenges of differential placebo effects in contemporary medicine: the example of brain stimulation. Ann Neurol 85(1):12–20

    Google Scholar 

  • Chae Y, Lee YS, Enck P (2018) How placebo needles differ from placebo pills? Front Psych 9:243

    Google Scholar 

  • Chey WD, Chey WY, Heath AT, Dukes GE, Carter EG, Northcutt A, Ameen VZ (2004) Long-term safety and efficacy of alosetron in women with severe diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol 99(11):2195–2203

    CAS  PubMed  Google Scholar 

  • Colagiuri B, Schenk LA, Kessler MD, Dorsey SG, Colloca L (2015) The placebo effect: from concepts to genes. Neuroscience 307:171–190

    CAS  PubMed  PubMed Central  Google Scholar 

  • Colloca L (2018a) Preface (part I). In: Neurobiology of the placebo effect part I. Academic Press, Cambridge, pp xv–xx

    Google Scholar 

  • Colloca L (2018b) Preface (part II). In: Neurobiology of the placebo effect part II. Academic Press, Cambridge, pp xvii–xxiii

    Google Scholar 

  • Colloca L, Benedetti F (2006) How prior experience shapes placebo analgesia. Pain 124(1–2):126–133

    PubMed  Google Scholar 

  • Colloca L, Petrovic P, Wager TD, Ingvar M, Benedetti F (2010) How the number of learning trials affects placebo and nocebo responses. Pain 151(2):430–439

    PubMed  PubMed Central  Google Scholar 

  • Dal-Re R, Janiaud P, Ioannidis JPA (2018) Real-world evidence: how pragmatic are randomized controlled trials labeled as pragmatic? BMC Med 16(1):49

    PubMed  PubMed Central  Google Scholar 

  • Darragh M, Booth RJ, Consedine NS (2014) Investigating the ‘placebo personality’ outside the pain paradigm. J Psychosom Res 76(5):414–421

    PubMed  Google Scholar 

  • De Allegri M, Pokhrel S, Becher H, Dong H, Mansmann U, Kouyate B, Kynast-Wolf G, Gbangou A, Sanon M, Bridges J, Sauerborn R (2008) 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

    PubMed  PubMed Central  Google Scholar 

  • de la Fuente-Fernandez R (2012) The powerful pre-treatment effect: placebo responses in restless legs syndrome trials. Eur J Neurol 19(10):1305–1310

    PubMed  Google Scholar 

  • Desai JR, Bowen EA, Danielson MM, Allam RR, Cantor MN (2013) Creation and implementation of a historical controls database from randomized clinical trials. J Am Med Inform Assoc 20(e1):e162–e168

    PubMed  PubMed Central  Google Scholar 

  • Diener HC, Dowson AJ, Ferrari M, Nappi G, Tfelt-Hansen P (1999) Unbalanced randomization influences placebo response: scientific versus ethical issues around the use of placebo in migraine trials. Cephalalgia 19(8):699–700

    CAS  PubMed  Google Scholar 

  • Elsenbruch S, Enck P (2015) Placebo effects and their determinants in gastrointestinal disorders. Nat Rev Gastroenterol Hepatol 12(8):472–485

    PubMed  Google Scholar 

  • Enck P, Klosterhalfen S (2019) Does sex/gender play a role in placebo and nocebo effects? Conflicting evidence from clinical trials and experimental studies. Front Neurosci 13:160

    PubMed  PubMed Central  Google Scholar 

  • Enck P, Lackner JM (2019) Cognitive behavioural therapy for IBS: results or treatment as usual? Nat Rev Gastroenterol Hepatol. In press. https://doi.org/10.1038/s41575-019-0174-2

    Google Scholar 

  • Enck P, Zipfel S (2019) Placebo effects in psychotherapy: a framework. Front Psych 10:456

    Google Scholar 

  • Enck P, Klosterhalfen S, Kruis W (2005a) Determination of placebo effect in irritable bowel syndrome. Dtsch Med Wochenschr 130(34–35):1934–1937

    CAS  PubMed  Google Scholar 

  • Enck P, Klosterhalfen S, Kruis W (2005b) Factors affecting therapeutic placebo response rates in patients with irritable bowel syndrome. Nat Clin Pract Gastroenterol Hepatol 2(8):354–355

    Google Scholar 

  • Enck P, Benedetti F, Schedlowski M (2008) New insights into the placebo and nocebo responses. Neuron 59(2):195–206

    CAS  PubMed  Google Scholar 

  • Enck P, Klosterhalfen S, Weimer K, Horing B, Zipfel S (2011a) The placebo response in clinical trials: more questions than answers. Philos Trans R Soc Lond Ser B Biol Sci 366(1572):1889–1895

    Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  • Enck P, Grundy D, Klosterhalfen S (2012) A novel placebo-controlled clinical study design without ethical concerns – the free choice paradigm. Med Hypotheses 79(6):880–882

    PubMed  Google Scholar 

  • Enck P, Bingel U, Schedlowski M, Rief W (2013a) The placebo response in medicine: minimize, maximize or personalize? Nat Rev Drug Discov 12(3):191–204

    CAS  PubMed  Google Scholar 

  • Enck P, Weimer K, Klosterhalfen S (2013b) Balanced placebo design, active placebos, and other design features for identifying, minimizing and characterizing the placebo response. In: Colloca L, Flaten MA, Meissner K (eds) Placebo and pain: from bench to bedside. Elsevier/Academic Press, Amsterdam, pp 159–173

    Google Scholar 

  • Enck P, Horing B, Broelz E, Weimer K (2018) Knowledge gaps in placebo research: with special reference to neurobiology. Int Rev Neurobiol 139:85–106

    PubMed  Google Scholar 

  • Enck P, Weimer K, Colloca L, Doods S (eds) (2019) Placebo and nocebo effects in psychiatry and beyond. Front Psychiatr. Research Topic https://www.frontiersin.org/research-topics/7727/placebo-and-nocebo-effects-in-psychiatry-and-beyond#articles

  • Faasse K, Cundy T, Gamble G, Petrie KJ (2013) The effect of an apparent change to a branded or generic medication on drug effectiveness and side effects. Psychosom Med 75(1):90–96

    CAS  PubMed  Google Scholar 

  • Fava M, Evins AE, Dorer DJ, Schoenfeld DA (2003) The problem of the placebo response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study design approach. Psychother Psychosom 72(3):115–127

    PubMed  Google Scholar 

  • FDA (2015) Mobile medical applications – guidance for industry and food and drug aministration staff. Federal Drug Administration, Silver Spring

    Google Scholar 

  • FDA (2016) Non-inferiority clinical trials to establish effectiveness – guidance for industy. Federal Drug Administration, Silver Spring

    Google Scholar 

  • Flight L, Julious SA (2016) Practical guide to sample size calculations: non-inferiority and equivalence trials. Pharm Stat 15(1):80–89

    PubMed  Google Scholar 

  • Ford AC, Moayyedi P (2010) Meta-analysis: factors affecting placebo response rate in the irritable bowel syndrome. Aliment Pharmacol Ther 32(2):144–158

    CAS  PubMed  Google Scholar 

  • Furukawa TA, Noma H, Caldwell DM, Honyashiki M, Shinohara K, Imai H, Chen P, Hunot V, Churchill R (2014) Waiting list may be a nocebo condition in psychotherapy trials: a contribution from network meta-analysis. Acta Psychiatr Scand 130(3):181–192

    CAS  PubMed  Google Scholar 

  • Geers AL, Wellman JA, Fowler SL, Helfer SG, France CR (2010) Dispositional optimism predicts placebo analgesia. J Pain 11(11):1165–1171

    PubMed  PubMed Central  Google Scholar 

  • Gold SM, Enck P, Hasselmann H, Friede T, Hegerl U, Mohr DC, Otte C (2017) Control conditions for randomised trials of behavioural interventions in psychiatry: a decision framework. Lancet Psychiatry 4(9):725–732

    PubMed  Google Scholar 

  • Grelotti DJ, Kaptchuk TJ (2011) Placebo by proxy. BMJ 343:d4345

    PubMed  PubMed Central  Google Scholar 

  • Grünbaum A (1986) The placebo concept in medicine and psychiatry. Psychol Med 16(1):19–38

    PubMed  Google Scholar 

  • Hall KT, Loscalzo J, Kaptchuk T (2018) Pharmacogenomics and the placebo response. ACS Chem Neurosci 9(4):633–635

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hesser H, Weise C, Rief W, Andersson G (2011) The effect of waiting: a meta-analysis of wait-list control groups in trials for tinnitus distress. J Psychosom Res 70(4):378–384

    PubMed  Google Scholar 

  • Horing B, Weimer K, Muth ER, Enck P (2014) Prediction of placebo responses: a systematic review of the literature. Front Psychol 5:1079

    PubMed  PubMed Central  Google Scholar 

  • Horing B, Weimer K, Muth ER, Enck P (2015) Prediction of symptom change in placebo versus no-treatment group in experimentally induced motion sickness. Appl Psychophysiol Biofeedback 40(3):163–172

    PubMed  Google Scholar 

  • Horing B, Newsome ND, Enck P, Babu SV, Muth ER (2016) A virtual experimenter to increase standardization for the investigation of placebo effects. BMC Med Res Methodol 16(1):84

    PubMed  PubMed Central  Google Scholar 

  • Irving G, Neves AL, Dambha-Miller H, Oishi A, Tagashira H, Verho A, Holden J (2017) International variations in primary care physician consultation time: a systematic review of 67 countries. BMJ Open 7(10):e017902

    PubMed  PubMed Central  Google Scholar 

  • Ivanova A, Tamura RN (2015) A two-way enriched clinical trial design: combining advantages of placebo lead-in and randomized withdrawal. Stat Methods Med Res 24(6):871–890

    PubMed  Google Scholar 

  • Jairath V, Zou G, Parker CE, Macdonald JK, Mosli MH, Khanna R et al (2016) Systematic review and meta-analysis: placebo rates in induction and maintenance trials of ulcerative colitis. J Crohns Colitis 10(5):607–618

    PubMed  PubMed Central  Google Scholar 

  • Jensen KB, Petrovic P, Kerr CE, Kirsch I, Raicek J, Cheetham A, Spaeth R, Cook A, Gollub RL, Kong J, Kaptchuk TJ (2014) Sharing pain and relief: neural correlates of physicians during treatment of patients. Mol Psychiatry 19(3):392–398

    CAS  PubMed  Google Scholar 

  • Jensen JS, Bielefeldt AO, Hrobjartsson A (2017) Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration: a methodological overview. J Clin Epidemiol 87:35–46

    PubMed  Google Scholar 

  • Jutte R (2013) The early history of the placebo. Complement Ther Med 21(2):94–97

    PubMed  Google Scholar 

  • Kaptchuk TJ (1998) Intentional ignorance: a history of blind assessment and placebo controls in medicine. Bull Hist Med 72(3):389–433

    CAS  PubMed  Google Scholar 

  • Kaptchuk TJ, Kelley JM, Deykin A, Wayne PM, Lasagna LC, Epstein IO, Kirsch I, Wechsler ME (2008) Do “placebo responders” exist? Contemp Clin Trials 29(4):587–595

    PubMed  Google Scholar 

  • Kelley JM, Lembo AJ, Ablon JS, Villanueva JJ, Conboy LA, Levy R, Marci CD, Kerr CE, Kirsch I, Jacobson EE, Riess H, Kaptchuk TJ (2009) Patient and practitioner influences on the placebo effect in irritable bowel syndrome. Psychosom Med 71(7):789–797

    PubMed  PubMed Central  Google Scholar 

  • Khan A, Redding N, Brown WA (2008) The persistence of the placebo response in antidepressant clinical trials. J Psychiatr Res 42(10):791–796

    PubMed  Google Scholar 

  • Khan S, Holbrook A, Shah BR (2018) Does Googling lead to statin intolerance? Int J Cardiol 262:25–27

    PubMed  Google Scholar 

  • Kirsch I (2000) Are drug and placebo effects in depression additive? Biol Psychiatry 47(8):733–735

    CAS  PubMed  Google Scholar 

  • Kirsch I (2014) The emperor’s new drugs: medication and placebo in the treatment of depression. Handb Exp Pharmacol 225:291–303

    CAS  PubMed  Google Scholar 

  • Kirsch I (2016) The placebo effect in the treatment of depression. Verhaltenstherapie 26:55–61

    Google Scholar 

  • Klosterhalfen S, Kellermann S, Pan F, Stockhorst U, Hall G, Enck P (2005a) Effects of ethnicity and gender on motion sickness susceptibility. Aviat Space Environ Med 76(11):1051–1057

    PubMed  Google Scholar 

  • Klosterhalfen S, Kellermann S, Stockhorst U, Wolf J, Kirschbaum C, Hall G, Enck P (2005b) Latent inhibition of rotation chair-induced nausea in healthy male and female volunteers. Psychosom Med 67(2):335–340

    PubMed  Google Scholar 

  • Klosterhalfen S, Pan F, Kellermann S, Enck P (2006) Gender and race as determinants of nausea induced by circular vection. Gend Med 3(3):236–242

    PubMed  Google Scholar 

  • Kobak KA (2010) Inaccuracy in clinical trials: effects and methods to control inaccuracy. Curr Alzheimer Res 7(7):637–641

    CAS  PubMed  Google Scholar 

  • Kobak KA, Kane JM, Thase ME, Nierenberg AA (2007) Why do clinical trials fail? The problem of measurement error in clinical trials: time to test new paradigms? J Clin Psychopharmacol 27(1):1–5

    PubMed  Google Scholar 

  • Krogsboll LT, Hrobjartsson A, Gotzsche PC (2009) Spontaneous improvement in randomised clinical trials: meta-analysis of three-armed trials comparing no treatment, placebo and active intervention. BMC Med Res Methodol 9:1

    PubMed  PubMed Central  Google Scholar 

  • Kronish IM, Hampsey M, Falzon L, Konrad B, Davidson KW (2018) Personalized (N-of-1) trials for depression: a systematic review. J Clin Psychopharmacol 38(3):218–225

    PubMed  PubMed Central  Google Scholar 

  • Leal Rato M, Duarte GS, Ferreira AN, Alves M, Mainoli B, Teodoro T, Mestre TA, Costa J, Ferreira JJ (2019) Nocebo response in Parkinson’s disease: a systematic review and meta-analysis. Parkinsonism Relat Disord. In press. https://doi.org/10.1016/j.parkreldis.2019.04.015

    Google Scholar 

  • Legrain V, Iannetti GD, Plaghki L, Mouraux A (2011) The pain matrix reloaded: a salience detection system for the body. Prog Neurobiol 93(1):111–124

    PubMed  Google Scholar 

  • Lipset CH (2014) Engage with research participants about social media. Nat Med 20(3):231

    CAS  PubMed  Google Scholar 

  • Liu Y, Rybin D, Heeren TC, Doros G (2019) Comparison of novel methods in two-way enriched clinical trial design. Stat Med. In press. https://doi.org/10.1002/sim.8288

    PubMed  Google Scholar 

  • Macaluso FS, Maida M, Ventimiglia M, Renna S, Cottone M, Orlando A (2018) Factors affecting clinical and endoscopic outcomes of placebo arm in trials of biologics and small molecule drugs in ulcerative colitis: a meta-analysis. Inflamm Bowel Dis 25(6):987–997

    Google Scholar 

  • Maddocks M, Kerry R, Turner A, Howick J (2016) Problematic placebos in physical therapy trials. J Eval Clin Pract 22(4):598–602

    PubMed  Google Scholar 

  • Mahr A, Golmard C, Pham E, Lordache L, Deville L, Faure P (2017) Types, frequencies, and burden of nonspecific adverse events of drugs: analysis of randomized placebo-controlled clinical trials. Pharmacoepidemiol Drug Saf 26(7):731–741

    CAS  PubMed  Google Scholar 

  • Mallinckrodt CH, Zhang L, Prucka WR, Millen BA (2010) Signal detection and placebo response in schizophrenia: parallels with depression. Psychopharmacol Bull 43(1):53–72

    PubMed  Google Scholar 

  • Mathie RT, Ulbrich-Zurni S, Viksveen P, Roberts ER, Baitson ES, Legg LA, Davidson JRT (2018) Systematic review and meta-analysis of randomised, other-than-placebo controlled, trials of individualised homeopathic treatment. Homeopathy 107(4):229–243

    PubMed  Google Scholar 

  • May M (2019) Twenty-five ways clinical trials have changed in the last 25 years. Nat Med 25(1):2–5

    CAS  PubMed  Google Scholar 

  • Moncrieff J, Wessely S, Hardy R (2004) Active placebos versus antidepressants for depression. Cochrane Database Syst Rev 1:Cd003012

    Google Scholar 

  • Moore RA, Wiffen PJ, Eccleston C, Derry S, Baron R, Bell RF, Furlan AD, Gilron I, Haroutounian S, Katz NP, Lipman AG, Morley S, Peloso PM, Quessy SN, Seers K, Strassels SA, Straube S (2015) Systematic review of enriched enrolment, randomised withdrawal trial designs in chronic pain: a new framework for design and reporting. Pain 156(8):1382–1395

    PubMed  Google Scholar 

  • Munkholm K, Paludan-Muller AS, Boesen K (2019) Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis. BMJ Open 9(6):e024886

    PubMed  PubMed Central  Google Scholar 

  • Papakostas GI, Fava M (2009) Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol 19(1):34–40

    CAS  PubMed  Google Scholar 

  • Quessy SN, Rowbotham MC (2008) Placebo response in neuropathic pain trials. Pain 138(3):479–483

    PubMed  Google Scholar 

  • Rakel DP, Hoeft TJ, Barrett BP, Chewning BA, Craig BM, Niu M (2009) Practitioner empathy and the duration of the common cold. Fam Med 41(7):494–501

    PubMed  PubMed Central  Google Scholar 

  • Rehn J, Schuster K (2017) Clinic design as placebo-using design to promote healing and support treatments. Behav Sci 7(4):E77

    PubMed  Google Scholar 

  • Relton C, Torgerson D, O’Cathain A, Nicholl J (2010) Rethinking pragmatic randomised controlled trials: introducing the “cohort multiple randomised controlled trial” design. BMJ 340:c1066

    PubMed  Google Scholar 

  • Rheker J, Rief W, Doering BK, Winkler A (2018) Assessment of adverse events in clinical drug trials: identifying amitriptyline’s placebo- and baseline-controlled side effects. Exp Clin Psychopharmacol 26(3):320–326

    CAS  PubMed  Google Scholar 

  • Rickels K, Lipman R, Raab E (1966) Previous medication, duration of illness and placebo response. J Nerv Ment Dis 142(6):548–554

    CAS  PubMed  Google Scholar 

  • Rief W, Nestoriuc Y, Weiss S, Welzel E, Barsky AJ, Hofmann SG (2009a) Meta-analysis of the placebo response in antidepressant trials. J Affect Disord 118(1–3):1–8

    CAS  PubMed  Google Scholar 

  • Rief W, Nestoriuc Y, von Lilienfeld-Toal A, Dogan I, Schreiber F, Hofmann SG, Barsky AJ, Avorn J (2009b) Differences in adverse effect reporting in placebo groups in SSRI and tricyclic antidepressant trials: a systematic review and meta-analysis. Drug Saf 32(11):1041–1056

    CAS  PubMed  Google Scholar 

  • Rutherford BR, Sneed JR, Roose SP (2009) Does study design influence outcome? The effects of placebo control and treatment duration in antidepressant trials. Psychother Psychosom 78(3):172–181

    PubMed  PubMed Central  Google Scholar 

  • Rutherford BR, Sneed JR, Tandler JM, Rindskopf D, Peterson BS, Roose SP (2011) Deconstructing pediatric depression trials: an analysis of the effects of expectancy and therapeutic contact. J Am Acad Child Adolesc Psychiatry 50(8):782–795

    PubMed  PubMed Central  Google Scholar 

  • Schedlowski M, Enck P, Rief W, Bingel U (2015) Neuro-bio-behavioral mechanisms of placebo and Nocebo responses: implications for clinical trials and clinical practice. Pharmacol Rev 67(3):697–730

    PubMed  Google Scholar 

  • Schoenfeld DA, Finkelstein DM, Macklin E, Zach N, Ennist DL, Taylor AA, Atassi N (2019) Design and analysis of a clinical trial using previous trials as historical control. Clin Trials. https://doi.org/10.1177/1740774519858914

    PubMed  Google Scholar 

  • Shaffer JA, Kronish IM, Falzon L, Cheung YK, Davidson KW (2018) N-of-1 randomized intervention trials in Health Psychology: a systematic review and methodology critique. Ann Behav Med 52(9):731–742

    PubMed  PubMed Central  Google Scholar 

  • Shah R, Ogden J (2006) ‘What’s in a face?’ The role of doctor ethnicity, age and gender in the formation of patients’ judgements: an experimental study. Patient Educ Couns 60(2):136–141

    PubMed  Google Scholar 

  • Shah E, Triantafyllou K, Hana AA, Pimentel M (2014) Adverse events appear to unblind clinical trials in irritable bowel syndrome. Neurogastroenterol Motil 26(4):482–488

    CAS  PubMed  Google Scholar 

  • Silverman RK, Ivanova A, Fine J (2018) Sequential parallel comparison design with binary and time-to-event outcomes. Stat Med 37(9):1454–1466

    PubMed  Google Scholar 

  • Spiller RC (1999) Problems and challenges in the design of irritable bowel syndrome clinical trials: experience from published trials. Am J Med 107(5a):91s–97s

    CAS  PubMed  Google Scholar 

  • Stein DJ, Baldwin DS, Dolberg OT, Despiegel N, Bandelow B (2006) Which factors predict placebo response in anxiety disorders and major depression? An analysis of placebo-controlled studies of escitalopram. J Clin Psychiatry 67(11):1741–1746

    CAS  PubMed  Google Scholar 

  • Stille G (1980) Preface. In: Handbook of experimental pharmacology, vol 55(I). Springer, Berlin, p V

    Google Scholar 

  • Suchman AL, Ader R (1992) Classic conditioning and placebo effects in crossover studies. Clin Pharmacol Ther 52(4):372–377

    CAS  PubMed  Google Scholar 

  • Torous J, Firth J (2016) The digital placebo effect: mobile mental health meets clinical psychiatry. Lancet Psychiatry 3(2):100–102

    PubMed  Google Scholar 

  • Tsui M, Rehal S, Jairath V, Kahan BC (2019) Most non-inferiority trials were not designed to preserve active comparator treatment effects. J Clin Epidemiol 110:82–89

    PubMed  Google Scholar 

  • Vambheim SM, Flaten MA (2017) A systematic review of sex differences in the placebo and the nocebo effect. J Pain Res 10:1831–1839

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ventriglio A, Magnifico G, Borraccino L, Rinaldi A, Bellomo A (2018) Placebo and cultural responses. Nord J Psychiatry 72(supp 1):S33–S35

    PubMed  Google Scholar 

  • Wang RS, Hall KT, Giulianini F, Passow D, Kaptchuk TJ, Loscalzo J (2017) Network analysis of the genomic basis of the placebo effect. JCI Insight 2(11):93911

    PubMed  Google Scholar 

  • Wartolowska K, Judge A, Hopewell S, Collins GS, Dean BJ, Rombach I, Brindley D, Savulescu J, Beard DJ, Carr AJ (2014) Use of placebo controls in the evaluation of surgery: systematic review. BMJ 348:g3253

    PubMed  PubMed Central  Google Scholar 

  • Waschbusch DA, Pelham WE Jr, Waxmonsky J, Johnston C (2009) Are there placebo effects in the medication treatment of children with attention-deficit hyperactivity disorder? J Dev Behav Pediatr 30(2):158–168

    PubMed  Google Scholar 

  • Wechsler ME, Kelley JM, Boyd IO, Dutile S, Marigowda G, Kirsch I, Israel E, Kaptchuk TJ (2011) Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N Engl J Med 365(2):119–126

    CAS  PubMed  PubMed Central  Google Scholar 

  • Weimer K, Enck P (2014) Traditional and innovative experimental and clinical trial designs and their advantages and pitfalls. Handb Exp Pharmacol 225:237–272

    PubMed  Google Scholar 

  • Weimer K, Gulewitsch MD, Schlarb AA, Schwille-Kiuntke J, Klosterhalfen S, Enck P (2013) Placebo effects in children: a review. Pediatr Res 74(1):96–102

    PubMed  Google Scholar 

  • Weimer K, Colloca L, Enck P (2015a) Age and sex as moderators of the placebo response – an evaluation of systematic reviews and meta-analyses across medicine. Gerontology 61(2):97–108

    PubMed  PubMed Central  Google Scholar 

  • Weimer K, Colloca L, Enck P (2015b) Placebo effects in psychiatry: mediators and moderators. Lancet Psychiatry 2(3):246–257

    PubMed  PubMed Central  Google Scholar 

  • Whalley B, Hyland ME, Kirsch I (2008) Consistency of the placebo effect. J Psychosom Res 64(5):537–541

    PubMed  Google Scholar 

  • White P, Lewith G, Hopwood V, Prescott P (2003) The placebo needle, is it a valid and convincing placebo for use in acupuncture trials? A randomised, single-blind, cross-over pilot trial. Pain 106(3):401–409

    PubMed  Google Scholar 

  • Wolf S (1959) The pharmacology of placebos. Pharmacol Rev 11:689–704

    CAS  PubMed  Google Scholar 

  • Zelen M (1979) A new design for randomized clinical trials. N Engl J Med 300(22):1242–1245

    CAS  PubMed  Google Scholar 

  • Zhu Z, Zhang L, Jiang J, Li W, Cao X, Zhou Z, Zhang T, Li C (2014) Comparison of psychological placebo and waiting list control conditions in the assessment of cognitive behavioral therapy for the treatment of generalized anxiety disorder: a meta-analysis. Shanghai Arch Psychiatry 26(6):319–331

    PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The assistence of Astrid Bahun from Bahun + Design for the artwork is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Internal Medicine VI: Psychosomatic Medicine and Psychotherapy , University Hospital Tübingen, Tübingen, Germany

    Paul Enck & Sibylle Klosterhalfen

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  1. Paul Enck
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Correspondence to Paul Enck .

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Editors and Affiliations

  1. Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA

    James E. Barrett

  2. Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, London, UK

    Clive P. Page

  3. Department of Pharmacology, Johannes Gutenberg University, Mainz, Rheinland-Pfalz, Germany

    Martin C. Michel

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Enck, P., Klosterhalfen, S. (2019). Placebos and the Placebo Effect in Drug Trials. In: Barrett, J., Page, C., Michel, M. (eds) Concepts and Principles of Pharmacology. Handbook of Experimental Pharmacology, vol 260. Springer, Cham. https://doi.org/10.1007/164_2019_269

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