Explore: The Journal of Science and Healing
Volume 3, Issue 6 , Pages 561-572 , November 2007

Rationale and Methods for a Trial Assessing Placebo, Echinacea, and Doctor-Patient Interaction in the Common Cold

  • Bruce Barrett, MD, PhD

      Affiliations

    • Department of Family Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI
    • Corresponding Author InformationCorresponding Author. Address: 777 S Mills, Madison WI 53715
  • ,
  • Dave Rakel, MD

      Affiliations

    • Department of Family Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI
  • ,
  • Betty Chewning, PhD

      Affiliations

    • School of Pharmacy, University of Wisconsin, Madison, WI
  • ,
  • Lucille Marchand, MD

      Affiliations

    • Department of Family Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI
  • ,
  • David Rabago, MD

      Affiliations

    • Department of Family Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI
  • ,
  • Roger Brown, PhD

      Affiliations

    • School of Nursing, University of Wisconsin, Madison, WI
  • ,
  • Jo Scheder, PhD

      Affiliations

    • Department of Human Development and Family Studies, University of Wisconsin, Madison, WI
  • ,
  • Raandi Schmidt, APNP

      Affiliations

    • Department of Family Medicine, School of Nursing, University of Wisconsin, Madison, WI
  • ,
  • James E. Gern, MD

      Affiliations

    • Department of Pediatrics, University of Wisconsin, Madison, WI
  • ,
  • Kerry Bone, Dip Phyto

      Affiliations

    • MediHerb, Warwick, Australia
    • School of Health, University of New England, Armidale, NSW Australia
  • ,
  • Gay Thomas, MA

      Affiliations

    • Department of Family Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI
  • ,
  • Shari Barlow

      Affiliations

    • Department of Family Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI
  • ,
  • James Bobula, PhD

      Affiliations

    • Department of Family Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI

References 

  1. Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials. New York, NY: Springer-Verlag; 1998;
  2. Guyatt GH, Rennie D. Users’ Guides to the Literature: A Manual for Evidence-Based Clinical Practice. Chicago, Ill: AMA Press; 2002;
  3. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med. 2000;342:1878–1886
  4. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med. 2000;342:1887–1892
  5. Kunz R, Oxman AD. The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials. BMJ. 1998;317:1185–1190
  6. McKee M, Britton A, Black N, McPherson K, Sanderson C, Bain C. Methods in health services research (Interpreting the evidence: choosing between randomised and non-randomised studies). BMJ. 1999;319:312–315
  7. Ottenbacher K. Impact of random assignment on study outcome: an empirical examination. Control Clin Trials. 1992;13:50–61
  8. Pocock SJ, Elbourne DR. Randomized trials or observational tribulations?. N Engl J Med. 2000;342:1907–1909
  9. Basoglu M, Marks I, Livanou M, Swinson R. Double-blindness procedures, rater blindness, and ratings of outcome: observations from a controlled trial. Arch Gen Psychiatry. 1997;54:744–748
  10. Berlin JA, Rennie D. Measuring the quality of trials: the quality of quality scales. JAMA. 1999;282:1083–1085
  11. Caspi O, Millen C, Sechrest L. Integrity and research: introducing the concept of dual blindness (How blind are double-blind clinical trials in alternative medicine?). J Altern Complement Med. 2000;6:493–498
  12. Devereaux PJ, Manns BJ, Ghali WA, et al. Physician interpretations and textbook definitions of blinding terminology in randomized controlled trials. JAMA. 2001;285:2000–2003
  13. Jadad-Bechara AR, Moore RA, Carrol D. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials. 1996;17:1–12
  14. Engel LW, Guess HA, Kleinman A, Kusek JW. The Science of the Placebo: Toward an Interdisciplinary Research Agenda. London, England: BMJ Books; 2002;
  15. Harrington A. The Placebo Effect: An Interdisciplinary Exploration. Cambridge, Mass: Harvard University Press; 1997;
  16. Moerman DE. Meaning, Medicine and the ‘Placebo Effect’. Cambridge, NY: Cambridge University Press; 2002;
  17. Kirsch I. How Expectancies Shape Experience. Washington, DC: American Psychological Association; 1999;
  18. Shapiro AK, Shapiro E. The Powerful Placebo: From Ancient Priest to Modern Physician. Baltimore, Md: Johns Hopkins University Press; 1997;
  19. Barrett B, Muller D, Rakel D, Rabago D, Marchand L, Scheder J. Placebo, meaning and health. Perspect Biol Med. 2006;49:178–198
  20. Grufferman S. Complexity and the Hawthorne effect in community trials. Epidemiology. 1999;10:209–210
  21. Hsueh Y. The Hawthorne experiments and the introduction of Jean Piaget in American industrial psychology, 1929-1932. Hist Psychol. 2002;5:163–189
  22. Wickstrom G, Bendix T. The “Hawthorne effect”–what did the original Hawthorne studies actually show?. Scand J Work Environ Health. 2000;26:363–367
  23. Mead N, Bower P. Patient-centredness: a conceptual framework and review of the empirical literature. Soc Sci Med. 2000;51:1087–1110
  24. Flocke SA, Miller WL, Crabtree BF. Relationships between physician practice style, patient satisfaction, and attributes of primary care. J Fam Pract. 2002;51:835–840
  25. Moerman D. Doctors and patients: the role of clinicians in the placebo effect. Adv Mind Body Med. 2003;19:14–22
  26. Roter DL, Hall JA. Studies of doctor-patient interaction. Ann Rev Public Health. 1989;10:163–180
  27. Stewart MA. Effective physician-patient communication and health outcomes: a review. Can Med Assoc J. 1995;152:1423–1433
  28. Barsky AJ, Saintfort R, Rogers M, Borus JF. Nonspecific medication side effects and the nocebo phenomenon. JAMA. 2002;287:622–627
  29. Bouchet C, Guillemin F, Briancon S. Nonspecific effects in longitudinal studies: impact on quality of life measures. J Clin Epidemiol. 1996;49:15–20
  30. Kirsch I. Specifying nonspecifics: psychological mechanisms of placebo effects. In:  Harrington A editors. The Placebo Effect: An Interdisciplinary Exploration. Cambridge Mass: Harvard University Press; 1997;p. 166–186
  31. Di Blasi Z, Harkness E, Ernst E, Georgiou A, Kleijnen J. Influence of context effects on health outcomes: a systematic review. Lancet. 2001;357:757–762
  32. Di Blasi Z, Kleijnen J. Context effects (Powerful therapies or methodological bias?). Eval Health Prof. 2003;26:166–179
  33. Thomas KB. General practice consultations: is there any point in being positive?. BMJ. 1987;294:1200–1203
  34. Barrett BP, Brown RL, Locken K, Maberry R, Bobula JA, D’Alessio D. Treatment of the common cold with unrefined echinacea: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2002;137:939–946
  35. Barrett B, Locken K, Maberry R, et al. The Wisconsin Upper Respiratory Symptom Survey: development of an instrument to measure the common cold. J Fam Pract. 2002;51:265–273
  36. Barrett B, Brown R, Mundt M, et al. The Wisconsin Upper Respiratory Symptom Survey is responsive, reliable, and valid. J Clin Epidemiol. 2005;58:609–617
  37. Barrett B, Brown R, Voland R, Maberry R, Turner R. Relations among questionnaire and laboratory measures of rhinovirus infection. Eur Respir J. 2006;28:358–363
  38. Barrett B, Mundt MP, Brown RE. Assessing important difference and responsiveness in common cold. Qual Life Res. In press.
  39. Barrett B, Vohmann M, Calabrese C. Echinacea for upper respiratory infection: evidence-based clinical review. J Fam Pract. 1999;48:628–635
  40. Caruso TJ, Gwaltney JM. Treatment of the common cold with echinacea: a structured review. Clin Infect Dis. 2005;40:807–810
  41. Giles JT, Palat CT, Chien SH, Chang ZG, Kennedy DT. Evaluation of Echinacea for treatment of the common cold. Pharmacotherapy. 2000;20:690–697
  42. Kligler B. Echinacea. Am Fam Physician. 2003;67:77–80
  43. Linde K, Barrett B, Wolkart K, Bauer R, Melchart D. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev. 2006;(1):CD000530
  44. Melchart D, Linde K, Fischer P, Kaesmayr J. Echinacea for preventing and treating the common cold. Cochrane Library. 2000;(Issue 4):
  45. Barrett B, Locken K, Maberry R, et al. The Wisconsin Upper Respiratory Symptom Survey: development of an instrument to measure the common cold. J Fam Pract. 2002;51:265–273
  46. Jackson GG, Dowling HF, Spiesman IG, Boand AV. Transmission of the common cold to volunteers under controlled conditions. Arch Intern Med. 1958;101:267–278
  47. Jackson GG, Dowling HF, Anderson TO, Riff L, Saporta J, Turck M. Susceptibility and immunity to common upper respiratory viral infections-the common cold. Ann Intern Med. 1960;55:719–738
  48. Jackson GG, Dowling HF, Muldoon RL. Present concepts of the common cold. Am J Public Health. 1962;52:940–945
  49. Balint M. Is the therapeutic nature of the patient-physician relationship being undermined?. Arch Intern Med. 2000;160:2257–2259
  50. Bass MJ, Buck C, Turner L, Dickie G, Pratt G, Robinson HC. The physician’s actions and the outcome of illness in family practice. J Fam Pract. 1986;23:43–47
  51. Brody H. Placebo response, sustained partnership, and emotional resilience in practice. J Am Board Fam Pract. 1997;10:72–74
  52. Charon R. The patient-physician relationship (Narrative medicine: a model for empathy, reflection, profession and trust). JAMA. 2001;286:1897–1902
  53. Chewning B, Sleath B. Medication decision-making and management: a client-centered model. Soc Sci Med. 1996;42:389–398
  54. Egbert LD, Battit GE, Welch CE, Bartlett MK. Reduction of post-operative pain by encouragement and instruction of patients. NEJM. 1964;270:825–827
  55. Kaplan SH, Greenfield S, Ware JE. Assessing the effects of physician-patient interactions on the outcomes of chronic disease. Med Care. 1989;27:S110–S127
  56. Krupat E, Bell RA, Kravitz RL, Thom D, Azari R. When physicians and patients think alike: patient-centered beliefs and their impact on satisfaction and trust. J Fam Pract. 2001;50:1057–1062
  57. Latham CE. Is there data to support the concept that educated, empowered patients have better outcomes?. J Am Soc Nephrol. 1998;9(suppl 4):S141–S144
  58. Levenstein JH, McCracken EC, McWhinney IR, Stewart MA, Brown JB. The patient-centred clinical method (1. A model for the doctor-patient interaction in family medicine). Fam Pract. 1986;3:24–30
  59. Pappas S, Perlman A. Complementary and alternative medicine (The importance of doctor-patient communication). Med Clin North Am. 2002;86:1–10
  60. Reilly D. Enhancing human healing. BMJ. 2001;322:120–121
  61. Roter DL, Hall JA, Kern DE, Barker LR, Cole KA, Roca RP. Improving physicians’ interviewing skills and reducing patients’ emotional distress (A randomized clinical trial). Arch Intern Med. 1995;155:1877–1884
  62. Simpson M, Buckman R, Stewart M, et al. Doctor-patient communication: the Toronto consensus statement. BMJ. 1991;303:1385–1387
  63. Starfield B, Wray C, Hess K, Gross R, Birk PS, D’Lugoff BC. The influence of patient-practitioner agreement on outcome of care. Am J Public Health. 1981;71:127–131
  64. Stewart M, Brown JB, Boon H, Galajda J, Meredith L, Sangster M. Evidence on patient-doctor communication. Cancer Prev Control. 1999;3:25–30
  65. Suchman AL, Markakis K, Beckman HB, Frankel R. A model of empathic communication in the medical interview. JAMA. 1997;277:678–682
  66. Thomas KB. The consultation and the therapeutic illusion. BMJ. 1978;1:1327–1328
  67. Roter DL, Hall JA, Merisca R, Nordstrom B, Cretin D, Svarstad B. Effectiveness of interventions to improve patient compliance: a meta-analysis. Med Care. 1998;36:1138–1161
  68. Roter DL, Hall JA. Doctors Talking with Patients: Patients Talking with Doctors: Improving Communication in Medical Visits. Westport Conn: Auburn House; 1992;
  69. Flood AB, Lorence DP, Ding J, McPherson K, Black NA. The role of expectations in patients’ reports of post-operative outcomes and improvement following therapy. Med Care. 1993;31:1043–1056
  70. Little P, Everitt H, Williamson I, et al. Observational study of effect of patient centredness and positive approach on outcomes of general practice consultations. BMJ. 2001;323:908–911
  71. Mondloch MV, Cole DC, Frank JW. Does how you do depend on how you think you’ll do? (A systematic review of the evidence for a relation between patients’ recovery expectations and health outcomes). Can Med Assoc J. 2001;165:174–179
  72. Petrie KJ, Weinman J, Sharpe N, Buckley J. Role of patients’ view of their illness in predicting return to work and functioning after myocardial infarcation: longitudinal study. BMJ. 1996;312:1191–1194
  73. Ryff CD. Positive mental health. In:  Blechman EA,  Brownell KD editor. Behavioral Medicine and Women: A Comprehensive Handbook. New York, NY: Guilford Publications, Inc; 1998;p. 183–188
  74. Savage R, Armstrong D. Effect of a general practitioner’s consulting style on patients’ satisfaction: a controlled study. BMJ. 1990;301:968–970
  75. Roter DL, Hall JA. Patient-provider communication. In:  Glanz K,  Lewis FM,  Rimer BK editor. Health Behavior and Health Education: Theory, Research and Practice. San Francisco, Calif: Jossey-Bass, A Wiley Company; 1997;p. 206–226
  76. Evans RG, Barer ML, Marmot TR. Why are Some People Healthy and Others Not? (The Determinants of Health in Populations). New York, NY: Aldine de Gruyter; 1994;
  77. Marmot MG. Social differentials in health within and between populations. Daedalus: J Am Acad Arts Sci. 1994;123:197–216
  78. McKnight JL. Health and empowerment. Can J Public Health. 1985;(suppl 1):37–38
  79. Singer B, Ryff CD. Hierarchies of life histories and associated health risk. Ann N Y Acad Sci. 1999;896:95–115
  80. Guadagnoli E, Ward P. Patient participation in decision-making. Soc Sci Med. 1998;47:329–339
  81. Suchman AL, Matthews DA. What makes the patient-doctor relationship therapeutic? (Exploring the connexional dimension of medical care). Ann Intern Med. 1988;108:125–130
  82. Matthews DA, Suchman AL, Branch WT. Making “connexions”: enhancing the therapeutic potential of patient-clinician relationships. Ann Intern Med. 1993;118:973–977
  83. Goldberg PE. The physician-patient relationship: three psychodynamic concepts that can be applied to primary care. Arch Fam Med. 2000;9:1164–1168
  84. Mercer SW, Reynolds WJ. Empathy and quality of care. Br J Gen Pract. 2002;52(suppl):S9–S12
  85. Mercer SW, McConnachie A, Maxwell M, Heaney D, Watt GCM. Relevance and practical use of the Consultation and Relational Empathy (CARE) Measure in general practice. Fam Pract. 2005;22:328–334
  86. Mercer SW, Maxwell M, Heaney D, Watt GCM. The consultation and relational empathy (CARE) measure: development and preliminary validation and reliability of an empathy-based consultation process measure. Fam Pract. 2004;21:699–705
  87. Hall JA, Horgan TG, Stein TS, Roter DL. Liking in the physician–patient relationship. Patient Educ Couns. 2002;48:69–77
  88. Badia LX, Herdman M, Schiaffino A. Determining correspondence between scores on the EQ-5D “thermometer” and a 5-point categorical rating scale. Med Care. 1999;37:671–677
  89. Coyle D, Wells G, Graham I, Lee KM, Peterson JE, Papadimitropoulos E. The impact of risk on preference values: implications for evaluations of postmenopausal osteoporosis therapy. Value Health. 2001;4:385–391
  90. Feeny D, Furlong W, Torrance GW, et al. Multiattribute and single-attribute utility functions for the health utilities index mark 3 system. Med Care. 2002;40:113–128
  91. Brazier JE, Harper R, Jones NMB, et al. Validating the SF-36 health survey questionnaire: new outcome measure for primary care. BMJ. 1992;305:160–164
  92. Jenkinson C, Wright L, Coulter A. Criterion validity and reliability of the SF-36 in a population sample. Qual Life Res. 1994;3:7–12
  93. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I (Conceptual framework and item selection). Med Care. 1992;30:473–483
  94. McHorney CA, Ware JE, Raczek AE. The MOS 36-item short-form health survey (SF-36): II (Psychometric and clinical tests of validity in measuring physical and mental health constructs). Med Care. 1998;31:247–263
  95. McHorney CA, Ware JE, Lu JFR, Sherbourne CD. The MOS 36-Item short-form health survery (SF-36): III (Tests of data quality, scaling assumptions, and reliability across diverse patient groups). Med Care. 1994;32:40–66
  96. Ware JE, Kosinski M, Dewey JE, Gandek B. How to Score and Interpret Single-Item Health Status Measures: A Manual for Users of the SF-8 Health Survey. Lincoln, RI: QualityMetric; 2001;
  97. Cobb JM, Steptoe A. Psychosocial stress and susceptibility to upper respiratory tract illness in an adult population sample. Psychosom Med. 1996;58:404–412
  98. Cohen S, Tyrell DAJ, Smith AP. Psychological stress and susceptibility to the common cold. NEJM. 1991;325:606–612
  99. Stone AA, Bovbjerg DH, Neale JM, et al. Development of common cold symptoms following experimental rhinovirus infection is related to prior stressful life events. Behav Med. 1992;18:115–120
  100. Takkouche B, Regueira C, Gestal-Otero JJ. A cohort study of stress and the common cold. Epidemiology. 2001;12:345–349
  101. Labbate LA, Fava M, Oleshansky M, Zoltec J, Littman A, Harig P. Physical fitness and perceived stress (Relationships with coronary artery disease risk factors). Psychosomatics. 1995;36:555–560
  102. Malarkey WB, Pearl DK, Demers LM, Kiecolt-Glaser JK, Glaser R. Influence of academic stress and season on 24-hour mean concentrations of ACTH, cortisol, and beta-endorphin. Psychoneuroendocrinology. 1995;20:499–508
  103. van Eck M, Nicolson NA. Perceived stress and salivary cortisol in daily life. Ann Behav Med. 1994;16:221–227
  104. van Eck M, Berkhof H, Nicolson N, Sulon J. The effects of perceived stress, traits, mood states, and stressful daily events on salivary cortisol. Psychosom Med. 1996;58:447–458
  105. Cohen S, Underwood LG, Gottlieb BH. Social Support Measurement and Intervention. Oxford, UK: Oxford University Press; 2000;
  106. Goodwin P, Leszcz M, Ennis M, et al. The effect of group psychosocial support on survival in metastatic breast cancer. NEJM. 2001;345:1719–1726
  107. Ryff CD, Singer B. Interpersonal flourishing: a positive health agenda for the new millenium. Pers Soc Psychol Rev. 2000;4:30–44
  108. Cohen S, Doyle WJ, Skoner DP, Rabin BS, Gwaltney JM. Social ties and susceptibility to the common cold. JAMA. 1997;277:1940–1944
  109. Ryff CD, Singer B. Psychological well-being: meaning, measurement, and implications for psychotherapy research. Psychother Psychosom. 1996;65:14–23
  110. Desharnais R, Godin G, Jobin J, Valois P, Ross A. Optimism and health-relevant cognitions after a myocardial infarction. Psychol Rep. 1990;67:t-5
  111. Ryff CD. Psychological well-being in adult life. Curr Dir Psychol Sci. 1995;4:99–104
  112. Schmutte PS, Ryff CD. Personality and well-being: reexamining methods and meanings. J Pers Soc Psychol. 1997;73:549–559
  113. Scheier MF, Carver CS. Optimism, coping, and health: assessment and implications of generalized outcome expectancies. Health Psychol. 1985;4:219–247
  114. Scheier MF, Carver CS. Effects of optimism on psychological and physical well-being: theoretical overview and empirical update. Cognit Ther Res. 1992;16:201–228
  115. Cohen S, Tyrrell DAJ, Smith AP. Negative life events, perceived stress, negative affect, and susceptibility to the common cold. J Pers Soc Psychol. 1993;64:131–140
  116. Cohen S, Doyle WJ, Skoner DP, Fireman P, Gwaltney JM, Newsom JT. State and trait negative affect as predictors of objective and subjective symptoms of respiratory viral infections. J Pers Soc Psychol. 1995;68:159–169
  117. Cohen S, Alper CM, Doyle WJ, Treanor JJ, Turner RB. Positive emotional style predicts resistance to illness after experimental exposure to rhinovirus or influenza a virus. Psychosom Med. 2006;68:809–815
  118. Albrecht RR, Ewing SJ. Standardizing the administration of the Profile of Mood States (POMS): development of alternative word lists. J Pers Assess. 1989;53:31–39
  119. Jacobs KW, Boze MM. Correlations among scales of the Beck Depression Inventory and the profile of mood states. Psychol Rep. 1993;73:431–434
  120. Little K, Penman E. Measuring subacute mood changes using the profile of mood states and visual analogue scales. Psychopathology. 1989;22:42–49
  121. Nyenhuis DL, Yamamoto C, Luchetta T, Terrien A, Parmentier A. Adult and geriatric normative data and validation of the profile of mood states. J Clin Psychol. 1999;55:79–86
  122. Pollock V, Cho DW, Reker D, Volavka J. Profile of Mood States: the factors and their physiological correlates. J Nerv Ment Dis. 1979;167:612–614
  123. Shacham S. A shortened version of the Profile of Mood States. J Pers Assess. 1983;47:305–306
  124. Abbas AK, Lichtman AH, Pober JS. Cellular and Molecular Immunology. Philadelphia, Pa: W.B. Saunders; 2000;
  125. Janeway CA, Travers P, Walport M, Capra JD. Immunobiology: the Immune System in Health and Disease. New York, NY: Current Biology Publications; 1999;
  126. Naclerio RM, Proud D, Lichtenstein LM, et al. Kinins are generated during experimental rhinovirus colds. J Infect Dis. 1988;157:133–142
  127. Teran LM, Johnston SL, Schroder JM, Church MK, Holgate ST. Role of nasal interleukin-8 in neutrophil recruitment and activation in children with virus induced asthma. Am J Respir Crit Care Med. 1997;155:1362–1366
  128. Turner RB. The treatment of rhinovirus infections: progress and potential. Antiviral Res. 2001;49:1–14
  129. Becker S, Koren HS, Henke DC. Interleukin-8 expression in normal nasal epithelium and its modulation by infection with respiratory syncytial virus and cytokines tumor necrosis factor, interleukin-1, and interleukin-6. Am J Respir Cell Mol Biol. 1993;8:20–27
  130. Kaul P, Biagioli MC, Singh I, Turner RB. Rhinovirus-induced oxidative stress and interleukin-8 elaboration involves p47-phox but is independent of attachment to intercellular adhesion molecule-1 and viral replication. J Infect Dis. 2000;181:1885–1890
  131. Choi AMK, Jacoby DB. Influenza virus A infection induces interleukin-8 gene expression in human airway epithelial cells. FEBS. 1992;309:327–329
  132. Garofalo R, Patel JA, Sim C, Schmalstieg FC, Goldman AS. Production of cytokines by virus-infected human respiratory epithelial cells. J Allergy Clin Immunol. 1993;91:177
  133. Gern JE, Vrtis R, Kelly EAB, Dick EC, Busse WW. Rhinovirus produces nonspecific activation of lymphocytes through a monocyte-dependent mechanism. J Immunol. 1996;157:1605–1612
  134. Johnston SL, Papi A, Monick MM, Hunninghake GW. Rhinoviruses induce interleukin-8 mRNA and protein production in human monocytes. J Infect Dis. 1997;175:323
  135. Noah TL, Henderson FW, Wortman IA, et al. Nasal cytokine production in viral acute upper respiratory infection of childhood. J Infect Dis. 1995;171:584–592
  136. Parry DE, Busse WW, Sukow KA, Dick CR, Swenson C, Gern JE. Rhinovirus-induced PBMC responses and outcome of experimental infection in allergic subjects. J Allergy Clin Immunol. 2000;105:692–698
  137. Roseler S, Holtappels G, Wagenmann M, Bachert C. Elevated levels of interleukins IL-1 beta, IL-6 and IL-8 in naturally acquired viral rhinitis. Eur Arch Otorhinolaryngol. 1995;1:S61–S63
  138. Zhu Z, Tang W, Gwaltney JM, Wu Y, Elias JA. Rhinovirus stimulation of interleukin-8 in vivo and in vitro: role of NF-kB. Am J Physiol. 1997;273:814–824
  139. Schroth MK, Grimm E, Frindt P, et al. Rhinovirus replication causes RANTES production in primary bronchial epithelial cells. Am J Respir Cell Mol Biol. 1999;20:1220–1228
  140. Mullins RJ, Heddle R. Adverse reactions associated with echinacea: the Australian experience. Ann Allergy Asthma Immunol. 2002;88:42–51
  141. Soon SL, Crawford RI. Recurrent erythema nodosum associated with Echinacea herbal therapy. J Am Acad Dermatol. 2001;44:298–299
  142. Taylor JA, Weber W, Standish L, et al. Efficacy and safety of echinacea in treating upper respiratory tract infections in children: a randomized controlled trial. JAMA. 2003;290:2824–2830
  143. Barrett B. Echinacea: a safety review. HerbalGram: J Am Botan. 2003;57:36–39
  144. Huntley AL, Thompson CJ, Ernst E. The safety of herbal medicinal products derived from echinacea species: a systematic review. Drug Safe. 2005;28:387–400
  145. Perri D, Dugoua JJ, Mills E, Koren G. Safety and efficacy of echinacea (E. angustafolia, e. purpurea and e. pallida) during pregnancy and lactation. Can J Clin Pharmacol. 2006;13:e262–e267
  146. Bentler PM. Multivariate analysis with latent variables: causual modeling. In:  Rosenzweig MR,  Porter LW editor. Annual Review of Psychology. Stanford, Conn: Annual Reviews, Inc; 1980;p. 419–456
  147. Browne MW. Covariance structures. In:  Hawkins DM editors. Topics in Applied Multivariate Analysis. Cambridge, Mass: Cambridge University Press; 1982;p. 72–141
  148. Dillon WR, Goldstein M. Multivariate Analysis: Methods and Applications. New York, NY: John Wiley & Sons; 1984;
  149. Huitema BE. The Analysis of Covariance and Alternatives. New York, NY: John Wiley & Sons; 1980;
  150. Joreskog KA. Analysis of covariance structures. Scand J Stat. 1981;8:65–92
  151. Lewontin R. Annotation: the analysis of variance and the analysis of causes. Am J Hum Genetics. 1974;26:400–411
  152. Snedecor GW, Cochran WG. Statistical Methods. Ames, IA: Iowa State University Press; 1980;
  153. Albert JM, DeMets DL. On a model-based approach to estimating efficacy in clinical trials. Stat Med. 1994;13:2323–2335
  154. Brown RL. Assessing specific mediational effects in complex theoretical models. Struct Eq Model. 1997;4:142–156
  155. Bryk AS, Raudenbush SW. Hierarchical Linear Models: Applications and Data Analysis Methods. Newbury Park, Calif: Sage; 1992;
  156. Davis CS. Semi-parametric and non-parametric methods for the analysis of repeated measurements with applications to clinical trials. Stat Med. 1991;1:1959–1980
  157. Goldstein H. Multilevel Statistical Models. New York, NY: Halsted; 1995;
  158. Hedeker D, Gibbons RD. A random-effects ordinal regression model for multilevel analysis. Biometrics. 1994;50:933–944
  159. Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika. 1986;73:13–22
  160. Littell RC, Milliken GA, Wolfinger RD. SAS System for Mixed Models. Cary, NC: SAS Institute, Inc; 1996;
  161. Stucki G, Daltroy L, Katz JN, Johannesson M, Liang MH. Interpretation of change scores in ordinal clinical scales and health status measures: the whole may not equal the sum of the parts. J Clin Epidemiol. 1995;49:711–717
  162. Friedman LM, Furberg CD, DeMets DL. Sample size. In: Fundamentals of Clinical Trials. New York, NY: Springer-Verlag; 1998;p. 94–129
  163. Gong J, Pinheiro JC, DeMets DL. Estimating significance level and power comparisons for testing multiple endpoints in clinical trials. Control Clin Trials. 2000;21:313–329
  164. Jaeschke R, Singer J, Guyatt GH. Measurement of health status: ascertaining the minimal clinically important difference. Control Clin Trials. 1989;10:407–415
  165. Guyatt GH, Bombardier C, Tugwell P. Measuring disease-specific quality of life in clinical trials. Can Med Assoc J. 1986;134:889–894
  166. Barrett B, Brown R, Mundt M, et al. Using benefit harm tradeoffs to estimate sufficiently important difference: the case of the common cold. Med Decis Making. 2005;25:47–55
  167. Barrett B, Brown D, Mundt M, Brown R. Sufficiently important difference: expanding the framework of clinical significance. Med Decis Making. 2005;25:250–261
  168. Barrett B, Harahan B, Brown D, Zhang Z, Brown R. Sufficiently important difference for common cold: severity reduction. Ann Fam Med. 2007;5:216–223
  169. Benjamini Y, Hochberg Y. On the adaptive control of the false discovery rate in multiple testing with independent statistics. J Educ Behav Stat. 2000;25:60–83
  170. Benjamini Y, Yekutieli D. Quantitative trait Loci analysis using the false discovery rate. Genetics. 2005;171:783–790
  171. Benjamini Y, Hochberg Y. Controlling the false discovery rate–a practical and powerful approach to multiple testing. J Roy Stat Soc. 1995;B57:289–300
  172. Hochberg Y, Benjamini Y. More powerful procedures for multiple significance testing. Stat Med. 1990;9:811–818
  173. Hedeker D, Gibbons RD. Application of random-effects pattern-mixture models for missing data in longitudinal studies. Psychol Methods. 1997;2:64–78
  174. Schafer JL. Analysis of Incomplete Multivariate Data. London, England: Chapman & Hall; 1997;
  175. Unnebrink K, Windeler J. Intention-to-treat methods for dealing with missing values in clinical trials of progressively deteriorating diseases. Stat Med. 2001;20:3931–3946
  176. Touloumi G, Babiker AG, Pocok SJ, Darbyshire JH. Impact of missing data due to drop-outs on estimators for rates of change in longitudinal studies A simulation study. Stat Med. 2001;20:3715–3728
  177. Little RJA. Modeling the drop-out mechanism in repeated-measures studies. J Am Stat Assoc. 1995;90:1112–1121
  178. Altman DG. Better reporting of randomised controlled trials: the CONSORT statement. BMJ. 1996;313:570–571
  179. Moher D, Schulz KF, Altman D. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA. 2001;285:1987–1991
  180. Ioannidis JP, Evans SJ, Gotzsche PC, et al. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med. 2004;141:781–788
  181. De Angelis CD, Drazen JM, Frizelle FA, et al. Is this clinical trial fully registered?–a statement from the International Committee of Medical Journal Editors. N Engl J Med. 2005;352:2436–2438
  182. Dickersin K, Rennie D. Registering clinical trials. JAMA. 2003;290:516–523
  183. Kaptchuk TJ. Powerful placebo: the dark side of the randomised controlled trial. Lancet. 1998;351:1722–1725
  184. Kaptchuk TJ. Intentional ignorance: a history of blind assessment and placebo controls in medicine. Bull Hist Med. 1998;72:389–433
  185. Kaptchuk TJ. The double-blind, randomized, placebo-controlled trial: gold standard or golden calf?. J Clin Epidemiol. 2001;54:541–549
  186. Kienle GS, Kiene H. The powerful placebo effect: fact or fiction?. J Clin Epidemiol. 1997;50:1311–1318
  187. Hrobjartsson A, Gotzsche PC. Is the placebo powerless? (An analysis of clinical trials comparing placebo with no treatment). N Engl J Med. 2001;344:1594–1602
  188. Walach H. The efficacy paradox in randomized controlled trials of CAM and elsewhere: beware of the placebo trap. J Altern Complement Med. 2001;7:213–218
  189. Di Blasi Z, Reilly D. Placebos in medicine: medical paradoxes need disentangling. BMJ. 2005;330:45

 This trial was supported by the National Center for Complementary and Alternative Medicine at the National Institutes of Health, grant NIH NCCAM 1-R01-AT-1428-01 (BB, JB, KB, RB, BC, DLD, LM, D. Rakel, D. Rabago, CDR). The University of Wisconsin School of Medicine and Public Health and the University of Wisconsin Department of Family Medicine have also contributed. Dr Barrett was supported by a K-23 career development grant from National Institutes of Health National Center for Complementary and Alternative Medicine a career development grant from the Robert Wood Johnson Foundation Generalist Physician Faculty Scholars Program.

 MediHerb supplied the echinacea and placebo tablets and conducted phytochemical analyses but did not contribute financially in any other way. MediHerb has no contractual right for involvement in data analysis, conclusions, or manuscript preparation.

PII: S1550-8307(07)00272-8

doi: 10.1016/j.explore.2007.08.001

Explore: The Journal of Science and Healing
Volume 3, Issue 6 , Pages 561-572 , November 2007