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Placebos: Their Underappreciated Impact in Pharmaceutical Trials

Terence W. Starz, MD, Theodore Pincus, MD, On Behalf Of The ARHP Practice Committee  |  Issue: September 2018  |  

In conclusion, placebo effects are experienced as real by patients, and further understanding of the impact of placebos in clinical research and care appears integral to optimal management of rheumatic diseases. New views of clinical trials are emerging (e.g., the Oxford Centre for Evidence-Based Medicine comments that “early hierarchies that placed randomized trials categorically above observational studies were criticized for being simplistic. In some cases, observational studies give us the ‘best’ evidence”).10 Recognition of these new views may be helpful in further understanding and harnessing the placebo effect to improve patient care and outcomes.21

Terence Starz, MD, is a clinical professor of medicine in the Division of Rheumatology at the University of Pittsburgh School of Medicine and is in practice at Arthritis and Internal Medicine Associates–UPMC in the Western Pennsylvania area.

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Theodore Pincus, MD, is a professor of medicine at Rush University Medical Center in Chicago.

References

  1. Kaptchuk TJ. Powerful placebo: The dark side of the randomised controlled trial. Lancet. 1998 Jun 6;351(9117):1722–1725.
  2. Berthelot JM. The placebo effect in rheumatology: New data. Joint Bone Spine. 2011 Mar;78(2):161–165.
  3. Zou K, Wong J, Abdullah N, et al. Examination of overall treatment effect and the proportion attributable to contextual effect in osteoarthritis: Meta-analysis of randomised controlled trials. Ann Rheum Dis. 2016 Nov;75(11):1964–1970.
  4. Zhang W, Robertson J, Jones AC, et al. The placebo effect and its determinants in osteoarthritis: Meta-analysis of randomised controlled trials. Ann Rheum Dis. 2008 Dec;67(12):1716–1723.
  5. Doherty M, Dieppe P. The ‘placebo’ response in osteoarthritis and its implications for clinical practice. Osteoarthritis Cartilage. 2009 Oct;17(10):1255–1262.
  6. Turner JA, Deyo RA, Loeser JD, et al. The importance of placebo effects in pain treatment and research. JAMA. 1994 May 25;271(20):1609–1614.
  7. Benedetti F, Carlino E, Piedimonte A. Increasing uncertainty in CNS clinical trials: The role of placebo, nocebo, and Hawthorne effects. Lancet Neurol. 2016 Jun;15(7):736–747.
  8. Hauser W, Sarzi-Puttini P, Tolle TR, Wolfe F. Placebo and nocebo responses in randomised controlled trials of drugs applying for approval for fibromyalgia syndrome treatment: Systematic review and meta-analysis. Clin Exp Rheumatol. 2012 Nov-Dec;30(6 Suppl 74):78–87.
  9. 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 Jul 11;347(2):81–88.
  10. Howick J. The Philosophy of Evidence-Based Medicine. Oxford: Wiley-Blackwell; 2011.
  11. Feinstein AR. An additional basic science for clinical medicine: II. The limitations of randomized trials. Ann Intern Med. 1983 Oct;99(4):544–550.
  12. Pincus T. Limitations of randomized clinical trials to recognize possible advantages of combination therapies in rheumatic diseases. Semin Arthritis Rheum. 1993 Oct;23(2 Suppl 1):2–10.
  13. Pincus T, Sokka T. Clinical trials in rheumatic diseases: Designs and limitations. Rheum Dis Clin North Am. 2004 Nov;30(4):701–724, v–vi.
  14. Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project. N Engl J Med. 1980 Oct;303(18):1038–1041.
  15. Ruberman W, Weinblatt E, Goldberg JD, Chaudhary BS. Psychosocial influences on mortality after myocardial infarction. N Engl J Med. 1984 Aug 30;311(9):552–559.
  16. Sokka T, Pincus T. Eligibility of patients in routine care for major clinical trials of anti-tumor necrosis factor alpha agents in rheumatoid arthritis. Arthritis Rheum. 2003 Feb;48(2):313–318.
  17. Sokka T, Abelson B, Pincus T. Mortality in rheumatoid arthritis: 2008 update. Clin Exp Rheumatol. 2008 Sep–Oct;26(5 Suppl 51):S35–S61.
  18. Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. Arthritis Rheum. 1990 Oct;33(10):1449–1461.
  19. Pincus T, Marcum SB, Callahan LF. Longterm drug therapy for rheumatoid arthritis in seven rheumatology private practices: II. Second line drugs and prednisone. J Rheumatol. 1992 Dec;19(12):1885–1894.
  20. Austin HA 3rd, Klippel JH, Balow JE, et al. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med. 1986 Mar 6;314(10):614–619.
  21. Bishop FL, Coghlan B, Geraghty AW, et al. What techniques might be used to harness placebo effects in non-malignant pain? A literature review and survey to develop a taxonomy. BMJ Open. 2017 Jun 30;7(6):e015516.

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