Der Anaesthesist

, Volume 57, Issue 5, pp 447–463

Klinische Bedeutung des Placeboeffektes

Leitthema

Zusammenfassung

Placebokontrollierte Studien sind heutzutage der „Goldstandard“ für die „evidenzbasierte Medizin“ in der Untersuchung klinischer Fragestellungen wie der Schmerztherapie. Dabei steht der Placeboeffekt nicht im eigentlichen Fokus des Interesses, sondern dient lediglich als Kontrolle für die Spezifität des Effektes einer bestimmten Behandlung. Was Mediziner häufig nicht erkennen, ist, dass der Placeboeffekt ein echtes, messbares Korrelat einer psychoneurobiologischen Reaktion des Organismus darstellt und damit selbst Einfluss auf den Heilungsprozess, wie z. B. die Schmerzlinderung, nehmen kann. Placebo ist also nicht gleichbedeutend mit „keine Therapie“. Placeboresponder, Ausmaß und Dauer des Placeboeffektes stellen keinen fixen Anteil dar, sondern unterliegen deutlich größerer Variabilität als bisher angenommen. Der Mythos, dass Placeboresponder eine bestimmte Persönlichkeit haben, hat sich nicht bestätigt, jedoch können das Arzt-Patient-Verhältnis und soziokulturelle Faktoren einen entscheidenden Einfluss auf den Placeboeffekt nehmen. Psychologische Erklärungsansätze zeigen, dass die klassische Konditionierung, die gesteigerte Erwartungshaltung und die Motivation des Patienten das Ausmaß des Placeboeffektes bestimmen. Diese wiederum können Einfluss auf neurobiologische Systeme nehmen, wie z. B. das endogene Opioidsystem, das entsprechend den modernen bildgebenden Verfahren v. a. in schmerzrelevanten Arealen aktiviert wird und zum Effekt der Placeboanalgesie beiträgt. Placeboeffekte, die in kontrollierten klinischen Studien bewusst vermieden werden sollen, können in der klinischen Praxis zur Optimierung des Gesamttherapieeffektes erwünscht sein. Dies sollte die Maximierung des situativen Kontexteffektes jeder therapeutischen Intervention zur Steigerung des Gesamttherapieeffektes – wie es in den neuesten Leitlinien der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) zur postoperativen Schmerztherapie empfohlen wird –, jedoch nicht die beabsichtigte isolierte Gabe einer inerten Substanz bedeuten. Letzteres ist rigorosen ethischen Richtlinien unterworfen und nur nach vorheriger Begutachtung durch die Ethikkommission im Rahmen von kontrollierten klinischen Studien möglich. Eine denkbare Alternative mag der von Benedetti vorgeschlagene Weg sein, bei dem die versteckte Gabe eines Verums den spezifischen Effekt identifiziert, im Gegensatz zur angekündigten Gabe desselben Verums, das den spezifischen und den Placeboeffekt charakterisiert, woraus man letztendlich das Ausmaß des Placeboeffektes bestimmen kann.

Schlüsselwörter

Placeboresponder Klassische Konditionierung Erwartungshaltung Motivation Endogenes Opioidsystem 

Clinical significance of the placebo effect

Abstract

Placebo controlled studies examining clinical problems, e.g. in pain therapy, are considered the „gold standard“ for evidence-based medicine. In these studies the placebo effect itself is not the main focus of interest, but serves more as a control for the specificity of the effect of a certain treatment. What physicans in this context often do not realize is that the placebo effect itself represents a true measurable correlate of an organism’s psycho-neurobiological response and, thereby, influences the healing process, e.g. the pain relief. Placebo is, therefore, not equivalent to „no treatment“. The number of placebo responders, the degree and the duration of the placebo effect is not fixed, but are subject to a much greater variability then hitherto believed. The myth that placebo responders have a certain personality has not been proven correct; instead, the relationships between physicians and patients as well as sociocultural factors have a considerable impact on the placebo effect. Psychological theories explain that classical conditioning, enhanced expectation and motivation of the patient determine the degree of the placebo effect. These directly influence neurobiological systems such as the endogenous opioids which according to modern brain imaging are predominantly activated in pain-relevant areas and contribute to the effect of placebo analgesia. Placebo effects that should be deliberately excluded in controlled clinical trials, can be desirable in clinical practice to optimize the total therapeutic effect. This should mean that the context effect of each therapeutic intervention is maximized towards an improved therapeutic effect, as outlined in the recent AWMF guidelines for postoperative pain therapy, but should not include the administration of an inert substance. The latter is controlled by rigorous ethical guidelines and is only permitted in the context of ethically approved controlled clinical trials. A possible alternative is suggested by Benedetti et al. in which the hidden administration of an active substance identifies the specific response in contrast to the open application of the same substance characterizing the specific plus the placebo effect, after which the pure placebo effect can be determined.

Keywords

Placebo responder Classical conditioning Expectational behavior Motivation Endogenous opioid system 

Literatur

  1. 1.
    Allan LG, Siegel L (2002) A signal detection theory analysis of the placebo effect. Eval Health Prof 25: 410–420PubMedGoogle Scholar
  2. 2.
    Amanzio M, Benedetti F (1999) Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci 19: 484–494PubMedGoogle Scholar
  3. 3.
    Amanzio M, Pollo A, Maggi G, Benedetti F (2001) Response variability to analgesics: a role for non-specific activation of endogenous opioids. Pain 90: 205–215PubMedGoogle Scholar
  4. 4.
    Asmar R, Safar M, Queneau P (2001) Evaluation of the placebo effect and reproducibility of blood pressure measurement in hypertension. Am J Hypertens 14: 546–552PubMedGoogle Scholar
  5. 5.
    Barrett B, Muller D, Rakel D et al. (2006) Placebo, meaning, and health. Perspect Biol Med 49: 178–198PubMedGoogle Scholar
  6. 6.
    Barsky AJ, Saintfort R, Rogers MP et al. (2002) Nonspecific medication side effects and the nocebo phenomenon. JAMA 287: 622–627PubMedGoogle Scholar
  7. 7.
    Beecher HK (1955) The powerful placebo. J Am Med Assoc 159: 1602–1606PubMedGoogle Scholar
  8. 8.
    Benedetti F (1996) The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain 64: 535–543PubMedGoogle Scholar
  9. 9.
    Benedetti F (2008) Mechanisms of placebo and placebo-related effects across diseases and treatments. Annu Rev Pharmacol Toxicol 48: 33–60PubMedGoogle Scholar
  10. 10.
    Benedetti F, Amanzio M, Maggi G (1995) Potentiation of placebo analgesia by proglumide. Lancet 346: 1231PubMedGoogle Scholar
  11. 11.
    Benedetti F, Arduino C, Amanzio M (1999) Somatotopic activation of opioid systems by target-directed expectations of analgesia. J Neurosci 19: 3639–3648PubMedGoogle Scholar
  12. 12.
    Benedetti F, Arduino C, Costa S et al. (2006) Loss of expectation-related mechanisms in Alzheimer’s disease makes analgesic therapies less effective. Pain 121: 133–144PubMedGoogle Scholar
  13. 13.
    Benedetti F, Colloca L (2004) Placebo-induced analgesia: methology, neurobiology, clinical use, and ethics. Rev Analgesia 7: 129–143Google Scholar
  14. 14.
    Benedetti F, Colloca L, Lanotte M et al. (2004) Autonomic and emotional responses to open and hidden stimulations of the human subthalamic region. Brain Res Bull 63: 203–211PubMedGoogle Scholar
  15. 15.
    Benedetti F, Colloca L, Torre E et al. (2004) Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nat Neurosci 7: 587–588PubMedGoogle Scholar
  16. 16.
    Benedetti F, Maggi G, Lopiano L et al. (2003) Open versus hidden medical treatment: the patient’s knowledge about a therapy affects the therapy outcome. Prev Treat 6: #Google Scholar
  17. 17.
    Benedetti F, Pollo A, Lopiano L et al. (2003) Conscious expectation and unconscious conditioning in analgesia, motor, and hormonal placebo/nocebo response. J Neurosci 43: 4315–4323Google Scholar
  18. 18.
    Blackwell B, Bloomfield SS, Buncher CR (1972) Demonstration to medical students of placebo responses and non-drug factors. Lancet 1: 1279–1282PubMedGoogle Scholar
  19. 19.
    Blech J (2005) Schattenseite der Medizin. Spiegel 35: 132–143Google Scholar
  20. 20.
    Blech J (2007) Wundermittel im Kopf. Spiegel 26: 135–144Google Scholar
  21. 21.
    Braithwaite A, Cooper P (1981) Analgesic effects of branding in treatment of headaches. BMJ 282: 1576–1578Google Scholar
  22. 22.
    Brody H (1982) The lie that heals: the ethics of giving placebos. Ann Intern Med 97: 112–118PubMedGoogle Scholar
  23. 23.
    Brody H (2000) The placebo response. Recent research and implications for family medicine. J Fam Pract 49: 649–654PubMedGoogle Scholar
  24. 24.
    Buckalew LW, Coffield KE (1982) An investigation of drug expectancy as a function of capsule color and size and preparation form. J Clin Psychopharmacol 2: 245–248PubMedGoogle Scholar
  25. 25.
    Chaput de Saintonge DM, Herxheimer A (1994) Harnessing placebo effects in health care. Lancet 344: 995–998Google Scholar
  26. 26.
    Charron J, Rainville P, Marchand S (2006) Direct comparison of placebo effects on clinical and experimental pain. Clin J Pain 22: 204–211PubMedGoogle Scholar
  27. 27.
    Chvetzoff G, Tannock IF (2003) Placebo effects in oncology. J Natl Cancer Inst 95: 19–29PubMedCrossRefGoogle Scholar
  28. 28.
    Clegg DO, Reda DJ, Harris CL (2006) Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 354: 795–808PubMedGoogle Scholar
  29. 29.
    Cobb LA, Thomas GI, Dillard DH et al. (1959) An evaluation of internal-mammary-artery ligation by a double-blind technic. N Engl J Med 260: 1115–1118PubMedGoogle Scholar
  30. 30.
    Colloca L, Benedetti F (2005) Placebos and painkillers: is mind as real as matter? Nat Rev Neurosci 6: 545–552PubMedGoogle Scholar
  31. 31.
    Colloca L, Lopiano L, Lanotte M, Benedetti F (2004) Overt versus covert treatment for pain, anxiety, and Parkinson’s disease. Lancet Neurol 3: 679–684PubMedGoogle Scholar
  32. 32.
    Coronary Drug Study Research Group (1980) Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project. N Engl J Med 303(18): 1038–1041Google Scholar
  33. 33.
    Crow R, Gage H, Hampson S et al. (1998) The role of expectations in the placebo effect and their use in the delivery of health care: a critical review. Health Technol Assess 3: 1–98Google Scholar
  34. 34.
    De Craen AJ, Kaptchuk TJ, Tijssen JG et al. (1999) Placebos and placebo effects in medicine: historical overview. J R Soc Med 92: 511–515Google Scholar
  35. 35.
    De Craen AJM, Moerman DE, Heisterkamp SH et al. (1999) Placebo effect in the treatment of duodenal ulcer. Br J Clin Pharmacol 48: 853–860Google Scholar
  36. 36.
    De Craen AJM, Tijssen JGP, de Gans J et al. (2000) Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos. J Neurol 247: 183–188Google Scholar
  37. 37.
    De Crean AJ, Roos PJ, de Vries AL et al. (1996) Effect of colour of drugs: systematic review of perceived effect of drugs and their effectiveness. BMJ 313: 1624–1626Google Scholar
  38. 38.
    De la Fuente-Fernandez R, Ruth TJ, Sossi V et al. (2001) Expectation and dopamin release: mechanism of the placebo effect in Parkinson’s disease. Science 293: 1164–1166Google Scholar
  39. 39.
    De Pascalis V, Chiarada C, Carotenuto E (2002) The contribution of suggestibility and expectation to placebo analgesic phenomenon in an experimental setting. Pain 96: 393–402Google Scholar
  40. 40.
    Diener HC, Dowson AJ, Ferrari M et al. (1999) Unbalanced randomization influences placebo response: scientific versus ethical issues around the use of placebo in migraine trials. Cephalalgia 19: 699–700PubMedGoogle Scholar
  41. 41.
    Doongaji DR, Vahia VN, Bharucha MP (1978) On placebos, placebo responses and placebo responders. J Postgrad Med 24: 147–157PubMedGoogle Scholar
  42. 42.
    Egbert LD, Battit GE, Welch CE et al. (1964) Reduction of postoperative pain by encouragement and instruction of patients: a study of physician-patient rapport. N Engl J Med 270: 825–827PubMedGoogle Scholar
  43. 43.
    Enck P, Klosterhalfen S, Kruis W (2005) Determination of placebo effect in irritable bowel syndrome. Dtsch Med Wochenschr 130: 1934–1937PubMedGoogle Scholar
  44. 44.
    Ernst E, Resch KL (1995) Concept of true and perceived placebo effects. BMJ 311: 551–553PubMedGoogle Scholar
  45. 45.
    Evans FJ (1974) The placebo response in pain reduction. Adv Neurol 74(4): 289–296Google Scholar
  46. 46.
    Feinstein AR (2002) Post-therapeutic response and therapeutic „style”: re-formulating the „placebo effect“. J Clin Epidemiol 55: 427–429PubMedGoogle Scholar
  47. 47.
    Fields H (2004) State-dependent opioid control of pain. Nat Rev Neurosci 5: 565–575PubMedGoogle Scholar
  48. 48.
    Frank JD (1997) Die Heiler: Wirkungsweisen psychotherapeutischer Beeinflussung. Vom Schamanismus bis zu den modernen Therapien. Klett-Cotta, StuttgartGoogle Scholar
  49. 49.
    Geers AL, Weiland PE, Kosbab K et al. (2005) Goal activation, expectations, and the placebo effect. J Pers Soc Psychol 89: 143–159PubMedGoogle Scholar
  50. 50.
    Gleidman LH, Gratt WH, Teitelbaum HA (1957) Some implications of conditional reflex studies for placebo research. Am J Psychiatry 113: 1103–1107Google Scholar
  51. 51.
    Goldstein AP (1962) Participant expectancies in psychotherapy. Psychiatry 25: 72–79PubMedGoogle Scholar
  52. 52.
    Gracely RH, Dubner R, Deeter WR et al. (1985) Clinican’s expectations influence placebo analgesia. Lancet 1: 43PubMedGoogle Scholar
  53. 53.
    Grenfell RF, Briggs AH, Holland WC (1961) A double blind study of the treatment of hypertension. JAMA 176: 124–128PubMedGoogle Scholar
  54. 54.
    Gryll SL, Kathan M (1978) Situational factors contributing to the placebo effect. Psychopharmacology 47: 253–261Google Scholar
  55. 55.
    Harkness EF, Ernst E (2000) The enigmatic placebo effect – A systematic review to define its determinants. Perfusion 13: 164–170Google Scholar
  56. 56.
    Hoffman GA, Harrington A, Fields HL (2005) Pain and the placebo: what we have learned. Perspect Biol Med 48: 248–265PubMedGoogle Scholar
  57. 57.
    Hróbjartsson A (1996) The uncontrollable placebo effect. Eur J Clin Pharmacol 50: 345–348PubMedGoogle Scholar
  58. 58.
    Hróbjartsson A (2002) What are the main methological problems in the estimations of placebo effects? J Clin Epidemiol 55: 430–435PubMedGoogle Scholar
  59. 59.
    Hróbjartsson A, Gotzsche P (2001) Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 344: 1594–1602PubMedGoogle Scholar
  60. 60.
    Hróbjartsson A, Gotzsche P (2004) Is the placebo powerless? Update of a systematic review with 52 new randomised trials comparing placebo with no treatment. J Intern Med 256: 91–100PubMedGoogle Scholar
  61. 61.
    Huskisson EC (1974) Simple analgesics for arthritis. BMJ 4: 196–200PubMedCrossRefGoogle Scholar
  62. 62.
    Ilnyckyi A, Shanahan F, Anlon PA et al. (1997) Quantification of the placebo response in ulcerative colitis. Gastroenterology 112: 1854–1858Google Scholar
  63. 63.
    Kaptchuk TJ (1998) Powerful placebo: the dark side of the randomized controlled trial. Lancet 351: 1722–1725PubMedGoogle Scholar
  64. 64.
    Kaptchuk TJ (2001) The double-blind, randomized, placebo-controlled trial: gold standard or golden calf? J Clin Epidemiol 54: 541–549PubMedGoogle Scholar
  65. 65.
    Kaptchuk TJ (2002) The placebo effect in alternative medicine: can the performance of a healing ritual have clinical significance? Ann Intern Med 136: 817–825PubMedGoogle Scholar
  66. 66.
    Kaptchuk TJ, Goldman P, Stone DA, Stason WB (2000) Do medical devices have enhanced placebo effects? J Clin Epidemiol 53: 786–792PubMedGoogle Scholar
  67. 67.
    Kaptchuk TJ, Stason WB, Davis RB et al. (2006) Sham device v. inert pill: randomised controlled trial of two placebo treatments. BMJ 332: 391–397PubMedGoogle Scholar
  68. 68.
    Kienle GS, Kiene H (1996) Placeboeffekt und Placebokonzept. Eine kritische methologische und konzeptionelle Analyse von Angaben zum Ausmaß des Placeboeffekts. Forsch Komplementarmed 3: 121–138Google Scholar
  69. 69.
    Kienle GS, Kiene H (1997) The powerful placebo effect. Fact or fiction? J Clin Epidemiol 50: 1311–1318PubMedGoogle Scholar
  70. 70.
    Kirsch J (1985) Response expectancy as a determinant of experience and behavior. Am Psychol 40: 1189–1202Google Scholar
  71. 71.
    Klinger R, Soost S, Flor H, Worm M (2007) Classical conditioning and expectancy in placebo hypoalgesia: a randomized controlled study in patients with atopic dermatitis and persons with healthy skin. Pain 128: 31–39PubMedGoogle Scholar
  72. 72.
    Klosterhalfen S (2007) Women respond to conditioning, and men to suggestion of nausea. Gastroenterology 132: A133fGoogle Scholar
  73. 73.
    Korczyn AD, Neufeld MY, Elian M (1994) Bacillus epilepticus: treatment of epilepsy by colectomy and vaccines. Neurology 44: 1965–1969PubMedGoogle Scholar
  74. 74.
    Lee S, Walker JR, Jakul L et al. (2004) 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: 10–19PubMedGoogle Scholar
  75. 75.
    Levine JD, Gordon NC, Fields HL (1978) The mechanism of placebo analgesia. Lancet 2: 654–657PubMedGoogle Scholar
  76. 76.
    Lewis JA, Jonsson B, Kreutz G et al. (2002) Placebo-controlled trials and the declaration of Helsinki. Lancet 359: 1337–1340PubMedGoogle Scholar
  77. 77.
    Lieberman R (1964) An experimental study of the placebo response and three different situations of pain. J Psychiatr Res 2: 233–246Google Scholar
  78. 78.
    Lindbaeck M, Sandvik E, Liodden K et al. (2003) Predictors for the white coat effect in general practice patients with suspected and treated hypertension. Br J Gen Pract 53: 790–793Google Scholar
  79. 79.
    Lipman JJ, Miller BE, Mays KS et al. (1990) Peak B endorphin concentration in cerebrospinal fluid: reduced in chronic pain patients and increased during the placebo response. Psychopharmacology 102: 112–116PubMedGoogle Scholar
  80. 80.
    Lloyd JW, Hughes JT, Davies-Jones GA (1972) Relief of severe intractable pain by barbotage of cerebrospinal fluid. Lancet 1: 354–355PubMedGoogle Scholar
  81. 81.
    Loder E, Goldstein R, Biondi D (2005) Placebo effects in oral triptan trials: the scientific and ethical rationale for continued use of placebo controls. Cephalalgia 25: 124–131PubMedGoogle Scholar
  82. 82.
    Macedo A, Farré M, Banos JE (2003) Placebo effect and placebos: what are we talking about? Some conceptual and historical considerations. Eur J Clin Pharmacol 59: 337–342PubMedGoogle Scholar
  83. 83.
    Macedo A, Farré M, Banos JE (2006) A meta-analysis of the placebo response in acute migraine and how this response may be influenced by some of the characteristics of clinical trials. Eur J Clin Pharmacol 62: 161–172PubMedGoogle Scholar
  84. 84.
    Margo CE (1999) The placebo effect. Surv Ophthalmol 44: 31–44PubMedGoogle Scholar
  85. 85.
    McQuay H, Carroll D, Moore A (1996) Variation in the placebo effect in randomised controlled trials of analgesics: all is as blind as it seems. Pain 64: 331–335PubMedGoogle Scholar
  86. 86.
    McQuay HJ, Moore RA (2005) Placebo. Postgrad Med J 81: 155–160PubMedGoogle Scholar
  87. 87.
    McRae C, Cherin E, Yamazaki TG et al. (2004) Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Arch Gen Psychiatry 61: 412–420PubMedGoogle Scholar
  88. 88.
    Miller FG, Rosenstein DL (2006) The nature and power of the placebo effect. J Clin Epidemiol 59: 331–335PubMedGoogle Scholar
  89. 89.
    Moerman DE, Jones WB (2002) Deconstructing the placebo effect and finding the meaning response. Ann Intern Med 136: 471–476PubMedGoogle Scholar
  90. 90.
    Moore RA, Gavaghan D, Tramer MR et al. (1998) Size is everything – Large amounts of information are needed to overcome random effects in estimating direction and magnitude of treatment effects. Pain 78: 209–216PubMedGoogle Scholar
  91. 91.
    Moseley JB, O’Malley K, Petersen NJ et al. (2002) A controlled trial of arthroscopic surgery for osteoarthrits of the knee. N Engl J Med 347: 81–88PubMedGoogle Scholar
  92. 92.
    Peck C, Coleman G (1991) Implications of placebo theory for clinical research and practice in pain management. Theor Med 12: 247–270PubMedGoogle Scholar
  93. 93.
    Pepper OH (1945) A note on the placebo. Am J Pharmacol 117: 409–412Google Scholar
  94. 94.
    Petrovic P, Kalso E, Petersson KM et al. (2002) Placebo and opioid analgesia – Imaging a shared neuronal network. Science 295: 1737–1740PubMedGoogle Scholar
  95. 95.
    Phil RO, Altman J (1971) An experimental analysis of the placebo effect. J Clin Pharmacol 11: 91–95Google Scholar
  96. 96.
    Pollo A, Amanzio M, Arslanian A et al. (2001) Response expectancies in placebo analgesia and their clinical relevance. Pain 93: 77–84PubMedGoogle Scholar
  97. 97.
    Portwich P (2005) Evidence-based medicine – Methode, Kritik und Nutzen für eine professionalisierte Handlungspraxis in der Medizin. Gesundheitswesen 67: 319–324PubMedGoogle Scholar
  98. 98.
    Price DD (2001) Assessing placebo effects without placebo groups: an untapped possibility? Pain 90: 201–203PubMedGoogle Scholar
  99. 99.
    Price DD, Craggs J, Verne GN et al. (2007) Placebo analgesia is accompanied by large reductions in pain-related activity in irritable bowel syndrome patients. Pain 127: 63–72PubMedGoogle Scholar
  100. 100.
    Price DD, Milling LS, Kirsch I et al. (1999) An analysis of factors that contribute to the magnitiude of analgesia in an experimental paradigm. Pain 83: 147–156PubMedGoogle Scholar
  101. 101.
    Reynaert C, Janne P, Delire V et al. (1995) To control or to be controlled? From health locus of control to morphine control during patient-controlled analgesia. Psychother Psychsom 64: 74–81Google Scholar
  102. 102.
    Reynaert C, Janne P, Vanse M et al. (1995) Clinical trials of antidepressants: the hidden face: where locus of control appears to play a key role in depression outcome. Psychopharmacology 119: 449–454PubMedGoogle Scholar
  103. 103.
    Rief W, Avorn J, Barsky AJ (2006) Medication-attributed adverse effects in placebo groups. Arch Intern Med 166: 155–160PubMedGoogle Scholar
  104. 104.
    Rollman GB (1977) Signal detection theory measurement of pain: a review and critique. Pain 3: 187–211PubMedGoogle Scholar
  105. 105.
    Ross M, Olson JM (1981) An expectation-attribution model of the effects of placebos. Psychol Rev 88: 408–437PubMedGoogle Scholar
  106. 106.
    Rothmann KJ, Michels KB (1994) The continuing unethical use of placebo controls. N Engl J Med 331: 394–398.Google Scholar
  107. 107.
    Sauro MD (2005) Endogenous opiates and the placebo effect: a meta-analytic review. J Psychsom Res 58: 115–120Google Scholar
  108. 108.
    Schönbächler G (2002) Psychoanalyse und Placebo. Forum Psychoanal 18: 142–149Google Scholar
  109. 109.
    Shapiro AK, Morris LA (1978) The placebo effect in medical and psychological therapies. In: Garfield SL, Bergin AE (eds) Handbook of psychotherapy and behaviour change. An empirical analysis. Wiley & Sons, New York, pp 369–410Google Scholar
  110. 110.
    Sinclair R, Cassuto J, Högström S et al. (1988) Topical anesthesia with lidocaine aerosol in the control of postoperative pain. Anesthesiology 68: 895–901PubMedGoogle Scholar
  111. 111.
    Skovlund E (1991) Should we tell trials patients that they might receive placebo? Lancet 337: 1041PubMedGoogle Scholar
  112. 112.
    Skovlund E, Fyllingen G, Landre H et al. (1991) Comparison of post-partum pain treatments using a sequential trial design. I: paracetamol versus placebo. Eur J Clin Pharmacol 40: 343–347PubMedGoogle Scholar
  113. 113.
    Skovlund E, Fyllingen G, Landre H et al. (1991) Comparison of post-partum pain treatments using a sequential trial design. II: naproxen versus paracetamol. Eur J Clin Pharmacol 40: 539–542PubMedGoogle Scholar
  114. 114.
    Sox HC Jr, Margulies J, Sox CH (1981) Psychologically mediated effects of diagnostic tests. Ann Intern Med 95: 680–685PubMedGoogle Scholar
  115. 115.
    Stamer UM, Grond S, Meier C (1999) Responders and non-responders to post-operative pain treatment: the loading dose predicts analgesic needs. Eur J Anaesthesiol 16: 103–110PubMedGoogle Scholar
  116. 116.
    Stolberg M (2006) Inventing the randomized double-blind trial: the Nuremberg salt test of 1835. J R Soc Med 99: 642–643PubMedGoogle Scholar
  117. 117.
    Su C, Lichtenstein GR, Krok K et al. (2004) A meta-analysis of the placebo response rates of remission and response in clinical trials of active Crohn’s disease. Gastroenterology 126: 1257–1269PubMedGoogle Scholar
  118. 118.
    Swank DJ, Swank-Bordewijk SC, Hop WC et al. (2003) Laparoscopic adhesiolysis in patients with chronic abdominal pain: a blinded randomized controlled multi-centre trial. Lancet 361: 1247–1251PubMedGoogle Scholar
  119. 119.
    Swartzman LC, Burkell J (1998) Expectations and the placebo effect in clinical drug trials: why we should not turn a blind eye to unblinding, and other cautionary notes. Clin Pharmacol Ther 64: 1–7PubMedGoogle Scholar
  120. 120.
    Talley NJ, Locke GR, Lahr BD, et al. (2006) Predictors of the placebo response in functional dyspepsia. Aliment Pharmacol Ther 23: 923–936PubMedGoogle Scholar
  121. 121.
    Tenery R, Rakatansky H, Riddick FA Jr et al. (2002) Surgical „placebo“ controls. Ann Surg 235: 303–307PubMedGoogle Scholar
  122. 122.
    Thomas KB, Cooke ID (1987) Successful treatment of asymptomatic endometriosis: does it benefit infertile women? BMJ 294: 1117–1119PubMedGoogle Scholar
  123. 123.
    Thomas KB (1987) General practice consultations: is there any point in being positive? BMJ (Clin Res Ed) 294: 1200–1202Google Scholar
  124. 124.
    Thomas KB (1994) The placebo in general practice. Lancet 344: 1066–1067PubMedGoogle Scholar
  125. 125.
    Tramèr MR, Reynolds DJ, Moore RA et al. (1998) When placebo controlled trials are essential and equivalence trials are inadequate. BMJ 317: 875–880PubMedGoogle Scholar
  126. 126.
    Turner JA, Deyo RA, Loeser JD et al. (1994) The importance of placebo effects in pain treatment and research. JAMA 271: 1609–1614PubMedGoogle Scholar
  127. 127.
    Ulrich RS (1984) View through a window may influence recovery from surgery. Science 224: 420–421PubMedGoogle Scholar
  128. 128.
    Van Leeuwen JH, Castro R, Busse M et al. (2006) The placebo effect in the pharmacologic treatment of patients with lower urinary tract symptoms. Eur Urol 50: 440–452Google Scholar
  129. 129.
    Vase L, Robinson ME, Verne GN, Price DD (2005) Increased placebo analgesia over time in irritable bowel syndrome (IBS) patients is associated with desire and expectation but not endogenous opioid mechanisms. Pain 115: 338–347PubMedGoogle Scholar
  130. 130.
    Vase L, Riley JL 3rd, Price DD (2002) A comparison of placebo-effects in clinical analgesic trials versus studies of placebo analgesia. Pain 99: 443–452PubMedGoogle Scholar
  131. 131.
    Vase L, Robinson ME, Verne GN et al. (2003) The contribution of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients. An empirical investigation. Pain 105: 17–25PubMedGoogle Scholar
  132. 132.
    Voudouris NJ, Peck CL, Coleman G (1985) Conditioned placebo responses. J Pers Social Psych 48: 47–53Google Scholar
  133. 133.
    Voudouris NJ, Peck CL, Coleman G (1989) Conditioned response models of placebo phenomena: further support. Pain 38: 109–116PubMedGoogle Scholar
  134. 134.
    Voudouris NJ, Peck CL, Coleman G (1990) The role of conditioning and verbal expectancy in the placebo response. Pain 43: 121–128PubMedGoogle Scholar
  135. 135.
    Wager TD, Rilling JK, Smith EE et al. (2004) Placebo-induced changes in fMRI in the anticipation and experience of pain. Science 303: 1162–1167PubMedGoogle Scholar
  136. 136.
    Walach H, Sadaghiani C, Dehm C, Bierman D (2005) The therapeutic effect of clinical trials: understanding placebo response rates in clinical trials – A secondary analysis. BMC Med Res Methodol 5: 26PubMedGoogle Scholar
  137. 137.
    Wampold BE, Minami T, Tierney SC et al. (2005) The placebo is powerful: estimating placebo effects in medicine and psychotherapy from randomized clinical trials. J Clin Psychol 61: 835–854PubMedGoogle Scholar
  138. 138.
    Wickramasekera J (1985) A condition response model of the placebo effect: predictions from the model. In: White L, Tursky B, Schwartz GF (eds) Placebo: theory, research and mechanisms. Guilford, New York, pp 255–287Google Scholar
  139. 139.
    Zöfel K (2007) Placebo: Warum Scheinmedikamente manchmal auch wirken. Welt Online. http://www.welt.de/wissenschaft/article1423936Google Scholar
  140. 140.
    Zubieta J-K, Smith YR, Bueller JA et al. (2001) Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science 293: 311–315PubMedGoogle Scholar

Copyright information

© Springer Medizin Verlag 2008

Authors and Affiliations

  1. 1.Klinik für Anaesthesiologie und operative IntensivmedizinCharité - Universitätsmedizin Berlin, Campus Benjamin FranklinBerlinDeutschland

Personalised recommendations