, Volume 4, Issue 3, pp 531–536 | Cite as

Placebo-controlled procedural trials for neurological conditions


Neurological disease has been a central focus in the ongoing ethical debate over the use of invasive placebo controls, especially sham surgery. The risk to research subjects and necessary use of deception involved in these procedures must be balanced against the methodological need to control for bias and the placebo effect. We review a framework formulated for the ethical assessment of sham surgery in the context of research evaluating novel procedures for neurological conditions. Special issues raised include the growing evidence of expectation and conditioning effects in a number of neurological diseases, the escalating scale of risk from different types of invasive placebo interventions, and the increasing use of cross-over designs, which allow a switch from placebo to active intervention without additional procedures.

Key Words

Placebo-controlled trials sham surgery cross-over ethics neurological procedures deception 


  1. 1.
    Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 2001;344: 710–719.CrossRefPubMedGoogle Scholar
  2. 2.
    Macklin R. The ethical problems with sham surgery in clinical research. N Engl J Med 1999;341: 992–996.CrossRefPubMedGoogle Scholar
  3. 3.
    Gillett GR. Unnecessary holes in the head. IRB Ethics Hum Rev 2001;23(6): 1–6.CrossRefGoogle Scholar
  4. 4.
    Albin RL. Sham surgery controls: intracerebral grafting of fetal tissue for Parkinson’s disease and proposed criteria for use of sham surgery controls. J Med Ethics 2002;28: 322–325.CrossRefPubMedGoogle Scholar
  5. 5.
    Beecher HK. Surgery as placebo: a qualitative study of bias. JAMA 1961;176: 1102–1107.PubMedGoogle Scholar
  6. 6.
    Cobb LA, Thomas GI, Dillard DH, Merendino KA, Bruce RA. An evaluation of internal-mammary-artery ligation by a double-blind technic. N Engl J Med 1959;260: 1115–1118.CrossRefPubMedGoogle Scholar
  7. 7.
    Dimond EG, Kittle CF, Crockett JE. Comparison of internal mammary artery ligation and sham operation for angina pectoris. Am J Cardiol 1960;5: 483–486.CrossRefPubMedGoogle Scholar
  8. 8.
    Moseley JB, O’Malley K, Petersen NJ, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med 2002;347: 81–88.CrossRefPubMedGoogle Scholar
  9. 9.
    Horng S, Miller FG. Is placebo surgery unethical? N Engl J Med 2002;347: 137–139.CrossRefPubMedGoogle Scholar
  10. 10.
    Horng S, Miller FG. Ethical framework for the use of sham procedures in clinical trials. Crit Care Med 2003;31(3 Suppl): S126–30.CrossRefPubMedGoogle Scholar
  11. 11.
    Miller FG. Sham surgery: an ethical analysis. Am J Bioeth 2003; 3: 41–48.PubMedGoogle Scholar
  12. 12.
    Kim SY, Frank S, Holloway R, Zimmerman C, Wilson R, Kieburtz K. Science and ethics of sham surgery: a survey of Parkinson disease clinical researchers. Arch Neurol 2005;62: 1357–1360.CrossRefPubMedGoogle Scholar
  13. 13.
    Prehn AW, Vawter DE, Gervais KG, et al. Studying neurosurgical implants for Parkinson disease: a question of design. Neurology 2006;67: 1503–1505.CrossRefPubMedGoogle Scholar
  14. 14.
    Boer GJ, Widner H. Clinical neurotransplantation: core assessment protocol rather than sham surgery as control. Brain Res Bull 2002; 58: 547–553.CrossRefPubMedGoogle Scholar
  15. 15.
    Polgar S, Ng J. Ethics, methodology and the use of placebo controls in surgical trials. Brain Res Bull 2005;67: 290–297.CrossRefPubMedGoogle Scholar
  16. 16.
    Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK. Neurobiological mechanisms of the placebo effect. J Neurosci 2005;25: 10390–10402.CrossRefPubMedGoogle Scholar
  17. 17.
    Weijer C. Comment: I need a placebo like I need a hole in the head. J Law Med Ethics 2002;30: 69–72.CrossRefPubMedGoogle Scholar
  18. 18.
    Litton P, Miller FG. A normative justification for distinguishing the ethics of clinical research from the ethics of medical care. J Law Med Ethics 2005;33: 566–574.CrossRefPubMedGoogle Scholar
  19. 19.
    Flum DR. Interpreting surgical trials with subjective outcomes: avoiding un SPORTsmanlike conduct. JAMA 2006;296: 2483–2485.CrossRefPubMedGoogle Scholar
  20. 20.
    Wager TD, Rilling JK, Smith EE, et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 2004; 303: 1162–1167.CrossRefPubMedGoogle Scholar
  21. 21.
    Benedetti F, Colloca L, Torre E, et al. Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nat Neurosci 2004;7: 587–588.CrossRefPubMedGoogle Scholar
  22. 22.
    De la Fuente-Fernandez R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ. Expectation and dopamine release: mechanism of the placebo effect in Parkinson’s disease. Science 2001;293: 1164–1166.CrossRefPubMedGoogle Scholar
  23. 23.
    Goebel MU, Trebst AE, Steiner J, et al. Behavioral conditioning of immunosuppression is possible in humans. FASEB J 2002; 16: 1869–1873.CrossRefPubMedGoogle Scholar
  24. 24.
    De la Fuente-Fernandez R, Schulzer M, Stoessl AJ. The placebo effect in neurological disorders. Lancet Neurol 2002;1: 85–91.CrossRefPubMedGoogle Scholar
  25. 25.
    Andrade DM, Zumsteg D, Hamani C, et al. Long-term follow-up of patients with thalamic deep brain stimulation for epilepsy. Neurology 2006;66: 1571–1573.CrossRefPubMedGoogle Scholar
  26. 26.
    Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283: 2701–2711.CrossRefPubMedGoogle Scholar
  27. 27.
    Bjorklund A, Dunnett SB, Brundin P, et al. Neural transplantation for the treatment of Parkinson’s disease. Lancet Neurol 2003;2: 437–445.CrossRefPubMedGoogle Scholar
  28. 28.
    Kupsch A, Benecke R, Muller J, et al. Pallidal deep-brain stimulation in primary generalized or segmentai dystonia. N Engl J Med 2006;355: 1978–1990.CrossRefPubMedGoogle Scholar
  29. 29.
    Nutt JG, Burchiel KJ, Comella CL, et al.; ICV GDNF Study Group. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 2003;60: 69–73.PubMedGoogle Scholar
  30. 30.
    London AJ. Reasonable risks in clinical research: a critique and a proposal for the integrative approach. Stat Med 2006;25: 2869–2885.CrossRefPubMedGoogle Scholar
  31. 31.
    Fregni F, Boggio PS, Valle AC, et al. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke 2006;37: 2115–2122.CrossRefPubMedGoogle Scholar
  32. 32.
    Fregni F, Otachi PT, Do Valle A, et al. A randomized clinical trial of repetitive transcranial magnetic stimulation in patients with refractory epilepsy. Ann Neurol 2006;60: 447–455.CrossRefPubMedGoogle Scholar
  33. 33.
    Sole-Padulles C, Bartres-Faz D, Junque C, et al. Repetitive transcranial magnetic stimulation effects on brain function and cognition among elders with memory dysfunction: a randomized sham-controlled study. Cereb Cortex 2006;16: 1487–1493.CrossRefPubMedGoogle Scholar
  34. 34.
    Fregni F, Boggio PS, Lima MC, et al. A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of central pain in traumatic spinal cord injury. Pain 2006;122: 197–209.CrossRefPubMedGoogle Scholar
  35. 35.
    Linde K, Streng A, Jurgens S, et al. Acupuncture for patients with migraine: a randomized controlled trial. JAMA 2005;293: 2118–2125.CrossRefPubMedGoogle Scholar
  36. 36.
    Miller FG, Kaptchuk TJ. Acupuncture trials and informed consent. J Med Ethics 2007;33: 43–44.CrossRefPubMedGoogle Scholar
  37. 37.
    Olanow CW, Goetz CG, Kordower JH, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 2003;54: 403–414.CrossRefPubMedGoogle Scholar
  38. 38.
    Lang AE, Gill S, Patel NK, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 2006;59: 459–466 [Erratum in: Ann Neurol 2006;60:747].CrossRefPubMedGoogle Scholar
  39. 39.
    Grady D. With lasers and daring, doctors race to save a young man’s brain. The New York Times (Final ed.). Dec 19, 2006. Sect. F:1 (col. 1).Google Scholar
  40. 40.
    Miller FG, Wendler D, Swartzman LC. Deception in research on the placebo effect. PLoS Med 2005;2: e262.CrossRefPubMedGoogle Scholar
  41. 41.
    Wendler D. Deception in medical and behavioral research: is it ever acceptable? Milbank Q 1996;74: 87–114.CrossRefPubMedGoogle Scholar
  42. 42.
    Weiner RL, Erker PV. The effects of prebriefing misinformed research participants on their attributions of responsibility. J Psychol 1986;120: 397–410.CrossRefGoogle Scholar
  43. 43.
    Miller FG, Kaptchuk TJ. Sham procedures and the ethics of clinical trials. J R Soc Med 2004;97: 576–578.CrossRefPubMedGoogle Scholar

Copyright information

© Springer New York 2007

Authors and Affiliations

  1. 1.Department of Brain and Cognitive SciencesMassachusetts Institute of TechnologyCambridge
  2. 2.Department of Clinical BioethicsNational Institutes of HealthBethesda

Personalised recommendations