Reflections

Science in the cultural context

A lthough Latin as a spoken language has died, the word

“placebo”––meaning “I will please”–– lives on, enjoying
wide usage among both scientists and non-scientists. It was
Placebo’s modern definition first appears in 1811, as “any
medicine adopted more to please than to benefit the patient.”
One can thus visualize a nineteenth century Harley Street
first preserved in the Roman Catholic vespers for the dead, physician, importuned by a patient he considers a hypochon-
in the recitation of Psalm 116:9. Literally, this verse reads driac, writing a prescription for “Placebo,” thus signaling the
“I will walk before the Lord in the lands of the living.” The apothecary to dispense a pill or a “draught” containing no
Vulgate, the first Latin translation of the Bible, renders the first medicinal ingredients. The patient, not understanding Latin,
verb as “Placebo,” presumably because one “walks” before would leave satisfied, and often would even feel that the
the deity by living and acting in a way that pleases Him. In medicine was helping.
English, in the fourteenth century, the verb was transmuted
into a noun meaning a toady, a flatterer, or a hanger-on (1, A brief yet highly informative paper on the placebo was pub-
2). In Chaucer’s Canterbury Tales there is a character named lished in 1945 by O.H. Perry Pepper, a Philadelphia physician
Placebo, who exemplifies this meaning by telling the protago- and professor of medicine (3). According to Pepper, placebos
nist exactly what he wants to hear (“The Merchant’s Tale”). were frequently prescribed in the nineteenth and early twenti-
eth centuries, although the word “placebo” never appeared on

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 The Problematic Placebo

prescriptions. All prescriptions placebo effect, and other studies have been adduced that
were written in Latin, thus deny its existence. Meanwhile, the placebo has taken on a
a doctor would often write new, essential role in the development of new drugs. These
Credit: Tennessee State Library and Archives

for some bitter or vile-tasting aspects of the placebo are explored below, referencing some
preparation with an impres- of the major publications on the subject.
sive Latin name, for example,
“Fluidextract Cimicifuga Can The Placebo Be Medicine?
Nigra.” This was not done to Intuitively, the placebo response must be psychosomatic––a
enjoy a private laugh at the result of what is vaguely called the mind-body interaction.
patient’s expense. Indeed, One of the first investigations into the mechanism of the
Pepper gives a number of placebo response was conducted by Louis Lasagna and col-
legitimate reasons for the leagues at the Massachusetts General Hospital in Boston
use of placebos. Pending a (5). They aimed to determine whether there was a subset of
O.H. Perry Pepper firm diagnosis, or while test patients who consistently responded to placebo, and how
results are awaited, a pla- such responders might differ from non-responding patients.
cebo would make the patient feel that some action was being They studied post-operative pain, a condition in which three
taken, thus soothing anxiety. In some cases, no medication or four of every ten patients experienced relief after injection
was required, but the patient would not be satisfied just to wait of a saline placebo. Lasagna and colleagues carried out a
for symptoms to subside. When the patient’s condition was two-part study under a rather complex protocol on a total
incurable, a placebo might postpone the need for sedatives or of 162 patients who had undergone general, gynecologic,
lesson the amount of opiates needed for pain relief (3). orthopedic, or urologic surgery. In sixty-nine patients who had
received at least two placebo injections, they evaluated the
Pepper considers placebo use to be part of the art of medi- consistency of the placebo response, with the following results:
cine, but notes that it was not mentioned in any of fourteen
editions of a standard text on therapeutics, published between Inconsistent reactors (placebo sometimes effective) 38 (55%)
1875 and 1908; nor could he find any listing of the topic Consistent reactors (all placebo doses effective) 11 (16%)
in his search of medical indexes. He remarked that placebo
Consistent non-reactors (placebo never effective) 20 (29%)
seems a word not to be mentioned “in polite society” (3).

As if to counteract this situation, a Conference on Therapy, Every patient was evaluated psychologically through patient
held in 1946, by Cornell Medical College and The New York interviews, nurse questionnaires, Rorschach test, Thematic
Hospital, was devoted to the subject of placebos (4). It was, Apperception Test, and IQ test. On average,
by then, generally accepted that placebos sometimes appear the IQs of responders and non-responders
to produce a therapeutic effect, or even an adverse effect– were identical. In the Rorschach test,
–both probably owing to psychological causes, including the six signs were found common to
power of suggestion. The notion that placebos have more 60% of responders but absent
effect on patients of low intelligence and little education was in all the non-responders. The
refuted by a conference participant who showed, by examples interviews revealed a number
from his practice, that bright, highly accomplished people are of significant differences
very suggestible, and thus, easily affected by placebos (4). between responders and
non-responders. The
Whereas much of the largely botanical materia medica former minimized their
in use in the 1940s was of little value, the succeeding six pain, liked everyone,
decades have brought a flood of new drugs having undeni- described their hospital
able pharmacologic effects. It seems unlikely that doctors care as “wonderful,”
could have deliberately prescribed placebos—within these were talkative during
last sixty years—especially as yesteryear’s paternalistic medi- interviews, and used
cine has been largely replaced by a patient-physician part- cathartics frequently.
nership. Nonetheless, the placebo has not faded away to an
archaic curiosity. It has been addressed in research papers Lasagna et al. concluded
and popular articles and has been the subject of many that placebo responders
books. Scientific studies have sought to explain the putative do differ from non-

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 Reflections

Credit: Mark Morelli

responders, but can only be identified by intensive interviews Beecher’s view has received more recent
and psychological testing, not by “off-the-cuff” impressions. support from a 1995 study by Ernst and
Resch (7). Taking a more sophisticated
Further, placebo responders are not whiners, are not typically approach, these investigators posited
of one sex, and not of any particular age bracket. Lasagna an important difference between true
et al. felt that consistent responders might be identified in and perceived placebo responses. Even
advance by Rorschach testing and presented the following absent any treatment a patient may
working hypothesis. “There is a certain psychologic set which improve for a number of reasons. These Louis Lasagna
predisposes to anticipation of pain relief and thus to a posi- include the natural course of the disease,
tive placebo response. The presence of the traits making this regression of symptom intensity toward the mean, other time-
set is probably not an all-or-none phenomenon but related effects on the patient (e.g., decrease in “white-coat
a graded one. Other factors…psychologic and hypertension” as patient becomes more at ease) or the doc-
non-psychologic, known and unknown, determine tor (e.g., physician becomes more skillful), or unidentified
whether or not a particular dose of placebo pro- concomitant interventions (e.g., hypertensive patients adopt
duces an effect on a given patient” (5). favorable lifestyle changes). Inclusion of a no-treatment arm
in a clinical trial would enable one to measure the true pla-
Henry K. Beecher, a colleague of Lasagna’s, cebo effect by subtracting no-treatment results from the per-
authored an influential paper titled “The Powerful ceived placebo results.
Placebo” (6) in which he examined fifteen clini-
cal reports and the placebo responses encoun- Ernst and Resch set out to analyze the results of studies which
tered therein. He states that the fifteen were included both a placebo arm and a no-treatment arm. Such
randomly selected; however, seven of them studies, it turns out, are rare. From all clinical trials and meta-
came from the Beecher-Lasagna group. These analyses published 1986 to 1994, they found only twelve
studies included 1,082 patients, in whom reporting both placebo and untreated groups. Their paper
placebo showed significant effectiveness in reports on six of these, studies that contained a rating of pain
35.2±2.2%. Beecher suggests the small stan- as a clinical endpoint. Comparing the placebo group and
dard error of the mean (2.2%) as evidence untreated group data, they found a substantial true placebo
that a fundamental common mechanism must response in four studies, a marginal effect in one, and no
underlie these results. Within the fifteen-study effect in one (7).
meta-analysis, placebo responses generally
occurred in 30%–40% of study patients. There The Powerful Placebo Under Attack
were, however, two “outliers”: a headache study Frequently cited during the fifty years following its publica-
with 52% placebo responses and a seasickness tion, Beecher’s “The Powerful Placebo” became a classic.
study with 58%. The placebo response, accepted as a real phenomenon,
was widely studied. Yet, some skeptical attitudes were also
Beecher also describes adverse reactions follow- voiced. In 1997, Kienle and Kiene, in Germany, undertook
ing placebo administration (later dubbed ”nocebo” to refute the entire concept of placebo response by critically
effects), and even objectively measurable changes examining the validity of Beecher’s paper (8). Although they
[such as adrenocorticotropic hormone (ACTH)-mimetic claimed to have analyzed 800 publications, they focused
effects on the cellular components of the blood] follow- on the same fifteen studies on which Beecher’s paper was
ing injection of normal saline. He posits that a disease based. They concluded that Beecher had “totally misinter-
symptom consists of two components––the symptom preted the trials,” and even accused him of misquotation in
itself (e.g., pain) and the patient’s “reaction or pro- ten of the fifteen trials he had analyzed. Kienle and Kiene
cessing component” (e.g., anxiety or fear). The latter argued that a variety of phenomena have been uncritically
component may be ameliorated by a placebo. To the attributed as placebo effects by Beecher and the subsequent
patient’s psyche, says Beecher, any medicine ordered clinicians who believed in the power of the placebo. Some
by the doctor represents the doctor saying “I will take of the factors which may produce the illusion of a placebo
care of you” (6). response are: spontaneous improvement (e.g., in the common
cold and many other ailments), fluctuation of symptom sever-
ity (i.e., especially prominent in chronic disease or chronic
pain), additional non-drug interventions (e.g., rest, hot baths,
diet), irrelevant response variables (e.g., using subjective feel-

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ings instead of objective measurements as endpoints), and response is irrelevant. The placebo group, or arm, is included
experimental subordination (i.e., patient’s desire to please the to cancel out all changes that are not the result of the treat-
caring physician by giving favorable answers to questions). ment under test. It has been suggested that the inactive
medicine (or “comparator”) in clinical drug studies should
Their view received support, inter alia, from Hrobiartsson more accurately be called a “dummy” tablet or capsule (14).
and Gotzsche (9) who reviewed randomized clinical trials However, the word “placebo” continues to be the overwhelm-
which included both a placebo and a no-treatment group. ing favorite, perhaps because no one likes to be associated
The placebos were not limited to dummy drugs and included with a dummy-controlled study.
physical (manipulations) or psychological (therapy sessions)
interventions. The review was based on thirty-two trials The double blind, randomized, placebo-controlled trial has
(total 3795 patients) with binary outcomes and eighty-two become the gold standard for proving effectiveness and
(total 4730 patients) with continuous outcomes. In binary safety of a potential new drug. The double blind study is also
outcomes, placebo showed no statistically significant effect used in food intolerance testing and even, to some extent, in
as compared to no treatment. In trials with continuous out- evaluating new surgical procedures (sham surgery being the
comes, placebo showed a beneficial effect which, however, control). Strong (14) has traced publications on the “blind” or
decreased with increasing sample size. There was also a “double blind” test procedure back to 1937, in a report on
small placebo benefit in the treatment of pain. The authors the use of theobromine and aminophylline for angina pectoris
concluded that the only justification for placebo use is in the by Harry Gold of Cornell. The technique was called simply
clinical trial setting (but not in a one-to-one patient-physician “blind” testing until 1950, when “double blind” became the
office visit). preferred designation, to make it clear that both the patient
and the research staff were blinded as to which drug the
Robert Temple, of the Food and Drug Administration (FDA) patient was being given (14).
[see (10)], in his review of the book The Placebo Response
and the Power of Unconscious Healing, calls Hrobiartsson’s The FDA does not require that every study include a placebo
paper a classic (11). Based on the systematic review reported control group, and indeed, there are instances where the
in that paper, Temple concludes “the best available data placebo is dispensed with. Antibiotics may be
thus suggest at most a small effect of placebo, best shown approved on the basis of comparison with
for pain, where at least the known endogenous endorphins an already accepted antibiotic agent.
provide some mechanistic explanation.” Drawing on his long Giving a placebo is unethical if other
experience in formulating new drug evaluation policy at the adequate, albeit imperfect, remedies
FDA, he states that even in settings where one might expect a exist for a given condition (15). Many
placebo effect, such as treatment of hypertension, when auto- orphan drugs are approved on the
mated blood pressure monitoring is used, there is essentially basis of historical controls, comparing
no effect in placebo groups. Temple’s main criticism of the the new drug’s effect with informa-
book under review was that the author seems to believe in tion accumulated in the past on the
the reality of the placebo effect (11). course of the disease if untreated (16).
Nevertheless, the placebo arm is a part of
Yet even this is not the last word. A recent JAMA editorial a great many clinical trials conducted for
titled “The Power of Hope” calls on physicians to establish US regulatory approval. Such trials have
and maintain a sense of hope in the patient. It cites neuroim- been criticized as proving merely that the
aging research showing that psychologic factors can stimu- new drug is “better than nothing,” which
late favorable brain physiologic responses, which the authors is indeed faint praise. On the other
say may account for elements of the placebo response (12). hand, pharmaceutical firms are loath
There is also ongoing discussion and study of a possible to compare their new compound to an
association of religious faith, or spirituality, with the process established drug, honoring the dictum
of healing (13). “don’t ask the question if you might
not like the answer.”
The Placebo In Clinical Trials
Although the nature, even the reality, of the placebo response Lately, much criticism of the active vs
continues to be debated, the placebo remains an indispens- placebo study model has centered
able tool in clinical research. In the placebo-controlled on the trial data for several widely
clinical trial, the presence or absence of a “true” placebo prescribed antidepressants approved

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 Reflections

between 1987 and 1999. A 2002 meta-analysis of the FDA experience less therapeutic effect, tending again to disad-
database of controlled trials concluded that these drugs dem- vantage the active drug. In this way, the final results of the
onstrated a clinically negligible advantage over placebo (17). trial may be skewed. The study staff, who know the expected
It has recently been suggested that the selective serotonin- side effects of the active drug, may penetrate the blind on
reuptake inhibitors (SSRIs) have no advantage over the largely this basis and unwittingly bias the results. Third, unstated
discarded benzodiazapines Librium and Valium, or even over expectations by both subject and staff. There is an expecta-
the old tranquilizer meprobamate. It is suggested that the phar- tion of benefit by both the subject and the staff. The staff,
maceutical industry has replaced the above tranquilizers, as knowing the study design, know how many active arms there
well as the superior tricyclic antidepressants and monoamine are. Suppose the trial involves two doses of the new drug,
oxidase (MAO) inhibitors, with the SSRIs simply because the one active drug control, and one placebo. This design would
latter are on-patent and thus more profitable (13). lead the staff to expect improvement in three of every four
patients. On the part of the subject, expectation of benefit is
Kirby et al. (18) attempted to analyze why often enhanced by over-sell of the investigational product dur-
randomized clinical trials in depression and ing the consent process or during an orientation session (18).
anxiety seem unable to distinguish active
drug from placebo. They blame what To avoid the effects of the site-subject interaction, Kirby (18),
they call the “site-subject interac- and others, have suggested a rather radical approach––the
tion,” a factor which is “triple blind” study. Not only are patient, physician, and
out of the study sponsor’s other study site personnel blinded, but the periodic evalua-
control. This interaction tion of the patient’s condition is done by an outside “rater.”
includes several charac- The rater is blinded by not being given access to the patient’s
teristics. First, a supportive chart, thus being unaware of any side effects or ancillary
environment. The quiet, patient data; not informed as to study design and randomiza-
supportive atmosphere of tion ratio; and allowed only minimal contact with the patient.
the clinic office, and the This may reduce to a minimum any subjective influences on
comforting attitude of the the rater’s activity, but it adds another level of artificiality to
physician and support staff the patient’s care, which itself may affect the validity of the
, often triggers a response study results.
independent of the drug
administered. Second, pen- Now that the placebo is exclusively a research tool, modern
etration of the blind. There is dictionaries have modified its definition to “an inert or innoc-
a very human tendency to try uous substance used especially in controlled experiments
to penetrate the blind. Patients testing the efficacy of another substance (as a drug)” (19).
are naturally desirous of know- By this, as well as by its original definition, the placebo is
ing whether they have been inert and inactive. Nevertheless, it has become the center of
randomly assigned to receive two complex controversies: the question whether non-material
the active drug or the placebo. factors can influence the healing process; and the question of
Based on how they are feel- how best to use it, if at all, in human clinical trials. The 1811
ing, they may decide this definition of the placebo is now approaching its bicentennial.
way or that way. If they The issues surrounding the placebo are unlikely to have been
decide erroneously in resolved when that anniversary year is reached.
favor of the active,
they may feel a favor- Addendum
able effect which will Continuing interest in the placebo and placebo effects is
tend to decrease evidenced by a newly published (2009) monograph titled
any advantage the Placebo Effects: Understanding the Mechanisms in Health
active possesses and Disease. The author, Fabrizio Benedetti, is Professor of
over the placebo. Clinical and Applied Physiology at the University of Turin
If they erroneously Medical School, as well as a consultant for the Placebo
decide that they Project at the National Institutes of Health (NIH). At Turin,
are receiving pla- he heads what is considered the foremost laboratory in the
cebo, they may world for the study of placebo effects. His group conducts

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 The Problematic Placebo

14. Strong III, F.C. The history of the double blind test and the placebo. J.
brain imaging studies, as well as other types of studies, to Pharm. Pharmacol. 51, 237–238 (1999).
elucidate placebo responses. 15. Lasagna, L. Review of A. Shapiro and E. Shapiro’s The Powerful
Placebo: From Ancient Priest to Modern Physician. N. Engl. J. Med. 338,
A review of Benedetti’s book in the New England Journal of 1236–1237 (1998).
Medicine notes that his approach to the subject is sophisti- 16. Nordenberg, T. The healing power of placebos. FDA Consumer 34 (11)
(2000).
cated, even-handed, and devoid of romanticism (20). His
17. Antonuccio, D.O., Burns, D.D., and Danton, W.G. Antidepressants. A
presentation of data on placebo effects is organized by triumph of marketing over science? Prevention & Treatment 5, Artl
organ systems, and also points out organ systems whose D25 (2002). (Article accessed at http://psycnet.apa.org/?fa=main.
response to placebo has been little studied thus far. Benedetti doiLanding&doi=10.1037/1522-3736.5.1.525c)
18. Kirby, L., Borwege, S., Christensen, J. et al. Reducing placebo response:
stresses that the standard randomized, double-blind, placebo
Triple blinding and setting expectations. Appl. Clin. Trials 14, 48–49
controlled clinical trial does not detect true placebo effects, (2005).
and states that multi-armed (possibly impracticable) studies 19. Webster’s New Collegiate Dictionary. Springfield, MA, G. & C. Merriam
would be required to answer key questions about placebos. Co., p.876 (1977).

doi:10.1124/mi.9.3.1 20. Brody, H.A. Review of F. Benedetti’s Placebo Effects: Understanding the
Mechanisms in Health and Disease. N. Eng. J. Med. 360, 1576–1577
(2009).

References
1. Brodeur, D.W. A short history of placebos. J. Amer. Pharm. Assoc. New Stanley Scheindlin, DSc,
Series 5, 642, 662 (1965). holds a BS in pharmacy from
2. The Oxford English Dictionary 2nd ed. Oxford, U.K., Clarendon Press, Temple University and gradu-
Vol. XI, p. 942 (1989).
ate degrees in pharmaceutical
3. Pepper, O.H.P. A note on the placebo. Trans. Stud. Coll. Physicians Phila.
13, 81–82 (1945).
chemistry from Philadelphia
4. Conference on Therapy. N.Y. J. Med. 46, 1718–1727 (1946). College of Pharmacy and
5. Lasagna, L., Mosteller, F., von Felsinger, J.M., and Beecher, H.K. A study Science (now University of
of the placebo response. Amer. J. Med. 16, 770–779 (1954). Sciences in Philadelphia). His
6. Beecher, H.K. The powerful placebo. JAMA 159, 1602–1606 (1955). academic research dealt with
7. Ernst, E. and Resch, K.L. Concept of true and perceived placebo effects. plant constituents and chemi-
BMJ 311, 551–553 (1995).
cal interactions of vitamins. In his pharmaceutical industry
8. Kienle, G.S. and Kiene, H. The powerful placebo effect: fact or fiction? J.
Clin. Epidemiol. 50, 1311–1318 (1997). career, he handled new drug formulation developments, and
9. Hrobiartsson, A. and Gotsche, P.C. Is the placebo powerless? An analy- later regulatory affairs, presiding over the filing of about
sis of clinical trials comparing placebo with no treatment. N. Eng. J. Med. 100 generic new drug applications and two innovative drug
344, 1594–1602 (2001).
applications. Now retired, his activities include volunteer
10. Temple, R. An Eye for Data. Mol. Interv. 4, 313–317 (2004).
work, consulting, and writing Reflections pieces for this jour-
11. Temple, R. Review of R. Kradin’s The Placebo Response and the Power
of Unconscious Healing. N. Engl. J. Med. 360, 646–647 (2009). nal. E-mail: stansch@verizon.net
12. Harris, J.C. and DeAngelis, C.D. The power of hope. JAMA 300, 2919–
2920 (2008).
13. Horwitz, A.V. Review of D. Herzberg’s Happy Pills in America: From
Miltown to Prozac; A. Tone’s The Age of Anxiety: A History of America’s
Turbulent Affair with Tranquilizers; and E. Shorter’s Before Prozac: The
Troubled History of Mood Disorders in Psychiatry. N. Engl. J. Med. 360,
841–844 (2009).

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