Placebos: Their Underappreciated Impact in Pharmaceutical Trials

Sir William Osler, the father of modern medicine, said “the desire to take medicine is perhaps the greatest feature that separates man from animal.” Determination of the benefit of a medication can be challenging and includes a number of factors, such as pharmacologic activities on the disease pathophysiology, pharmacokinetic properties and patient characteristics.^1,2 An additional, often unrecognized or unappreciated, contributor, the placebo effect, also may be extraordinarily important in determining the response to a medication.³

At funerals in the Middle Ages, a common part of the funeral chant used by hired mourners (inauthentic behavior) began with the ninth verse of Psalm 116, Placebo Domino in regione vivorum, which in the Latin Vulgate translation means “I shall please the Lord in the land of the living.” This inauspicious connotation of placebo, representing falsehood, persisted, and the term was subsequently employed medically starting in the late 1700s to describe fake treatments given for a variety of diseases.

In that era of therapeutic adventure and misadventure, the cure—in widespread and unregulated use—was frequently worse than the illness (e.g., major surgery without anesthesia; use of powerful electrical devices). As a result, kinder and gentler interventions were often tried. It was recognized that treatments with inert substances, such as sugar or bread pills, and highly diluted preparations, such as used in homeopathy, could be associated with clinical benefit. Was this effect just the body’s natural healing processes, or was something else involved? Since that time, placebos have been used both therapeutically and as important methodologic tools in research.

Placebo is defined as an inert substance with no measurable biological effect that is used to please an individual rather than to provide a pharmacological effect on a disorder. A placebo group is included in clinical trials to help differentiate pharma­ceutical effects of an active intervention from nonpharmaceutical effects resulting from the natural course of disease, inherent healing processes, patient expectations of the treatment, messages conveyed by the doctor and others.^3,4

When patients in routine clinical care report that a certain medication is of no value and/or even makes them feel worse, they should not be told the treatment should be efficacious on the basis of reported evidence. The evidence is reported for patient groups, while individual patients often differ widely in responses to treatments or placebos.

Research Says …

Considerable debate and research exists concerning placebo and nocebo (negative placebo) effects in clinical trials involving rheumatic diseases, particularly osteoarthritis (OA), low back pain, depression and fibromyalgia, in which symptoms are affected by neural processing in specific areas of the brain.^5-8

An analysis of 215 OA clinical trials with more than 40,000 participants indicated that 75% of pain reduction could be attributed to “contextual effects,” including patient baseline status, expectations, beliefs and compliance; clinician behaviors, such as healing rituals, verbal suggestions and therapeutic touch; attractiveness of a treatment site; and many other effects.³ Placebo responses in OA are highest for invasive procedures, such as joint injections, intermediate for pills and least for topical agents.³ One surgical trial reported similar modest responses of OA patients to arthroscopic lavage, debridement and sham surgery; differences were neither statistically nor clinically significant.⁹

The importance of placebo responses highlights recognition of more general limitations of clinical trials, which often are ignored in medical education and communication, based on a belief that clinical trials invariably provide the best evidence concerning a therapy compared with another therapy or placebo.¹⁰ Randomized, double-blind, controlled clinical trials remain the optimal method to analyze the efficacy and safety of a therapy, mimicking a laboratory reductionist experiment to focus on a single variable—an active treatment vs. a control—while attempting to keep all other conditions identical.¹¹ That goal is met most effectively in short-term trials of an external pathogen, but is less achievable in longer trials involving chronic diseases.^12,13

Two early clinical trials in cardiovascular disease illustrate complexities in inter­pretation of placebo results. A trial to analyze clofibrate (to reduce cholesterol) vs. placebo to prevent death from cardiovascular disease indicated 15% five-year mortality in greater than 80% of patients who took clofibrate vs. 25% in those who did not, but also 15% mortality in greater than 80% of patients who took placebo vs. 28% in those who did not.¹⁴ Therefore, much better (and similar) results were seen in compliant vs. non-compliant patients, regardless of allocation to active vs. placebo treatment.¹⁴

In another clinical trial over three years to prevent cardiovascular death after acute myocardial infarction by a beta blocker or placebo (BHAT study), mortality was 9% in patients randomized to a beta blocker vs. 13% in those randomized to placebo, a statistically significant difference.15 However, in secondary analyses, mortality was 5%, 7% and 13% in patients with more than 12, 10–12 and fewer than 10 years of formal education, regardless of treatment allocation.¹⁵ These results were further explained by life stress and social isolation; mortality was 15% in patients with high levels of both, 7% with either and 2% with neither. The data indicate again that patient characteristics and behaviors were far more significant to outcomes than allocation to active treatment vs. placebo.¹⁵

The Limitations

Important pragmatic limitations are seen in clinical trials involving chronic rheumatic diseases.¹² One limitation is that inclusion and exclusion criteria usually restrict the number of participating patients to a small fraction of those with a given diagnosis; for example, at one site, only 5% of rheumatoid arthritis (RA) patients were eligible for the first study of infliximab in RA.¹⁶ Another limitation is that short-term surrogate measures may not predict long-term undesirable outcomes (e.g., a tender joint count is a poor predictor of long-term work disability and premature death in RA).¹⁷

The need for surrogate measures emerges from an important pragmatic limitation of most trials in chronic diseases: The observation period is relatively short compared with required, long-term (often lifetime) treatment. For example, a meta-analysis of 66 clinical trials reported in 1990 indicated the efficacy of methotrexate in RA was indistinguishable from injectable gold salts, penicillamine and azathioprine.¹⁸

In contrast, a study of 1,077 disease-modifying anti-rheumatic drug (DMARD) courses over five years at seven rheumatology care settings indicated that more than 50% of methotrexate courses were continued over five years vs. fewer than 20% of courses of other DMARDs.¹⁹ However, over one year, results for all DMARDs in the same patients were indistinguishable, as in clinical trials.¹⁹ Therefore, five-year effectiveness of methotrexate vs. other DMARDs was considerably higher; whereas, one-year efficacy was similar for all DMARDs.

Another example of important differences between short-term and long-term results involves the National Institutes of Health clinical trial in systemic lupus erythematosus (SLE) nephritis, which established cyclophosphamide as the standard of care for several decades.²⁰ Significantly greater renal survival was seen over 10 years in patients treated with cyclophosphamide rather than prednisone. But no differences were seen between treatment groups after three years, and differences were marginal even after five years.²⁰ The data raise consideration that some recently reported negative trials in SLE, vasculitis, systemic sclerosis and other diseases over one year may document significant benefit if longer periods were studied.

Even if all pragmatic limitations could be overcome, placebo-controlled clinical trials include intrinsic limitations not widely recognized.^12,13 One is that results are reported in groups, but some individual participants do not fit the pattern of the group. In most trials of pain control, some individuals report greater efficacy of placebo than an active treatment reported as, statistically, significantly superior to placebo in patient groups. Therefore, when patients in routine clinical care report that a certain medication is of no value and/or even makes them feel worse, they should not be told the treatment should be efficacious on the basis of reported evidence. The evidence is reported for patient groups, while individual patients often differ widely in responses to treatments or placebos.

Another intrinsic limitation of placebo-controlled clinical trials is that placebo and nocebo effects may be affected by the methodology itself.¹³ A patient who is told they are receiving the best available treatment may be more likely to respond than a patient who is told they are receiving a treatment in a research study intended to analyze responses to a drug compared with a placebo. Although the placebo control should adjust for differences, stronger treatments are recognized to elicit stronger place­bo responses.³

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.

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.