To Use Or Not To Use The Term “Placebo,” That Is (Not) The Question

Placebos have been around forever, even if they were not named as such. Just think about the stone age, when healers operated with mostly, if not exclusively, placebos, but did not call them that. Today, the term is rather popular (even a pop band is named that way), but it has a negative taste as well – why?

“Like the word dirge, placebo has its origin in the Office of the Dead, the cycle of prayers traditionally sung or recited for the repose of the souls of the dead. The traditional liturgical language of the Roman Catholic Church is Latin, and in Latin, the first word of the first antiphon of the vespers service is placebo, “I shall please.” This word is taken from a phrase in the psalm text that is recited after the antiphon, placebo Domino in regione vivorum“,”I shall please the Lord in the land of the living.” The vespers service of the Office of the Dead came to be called placebo in Middle English, and the expression sing placebo came to mean “to flatter, be obsequious.” … Placebo eventually came to mean “flatterer” and “sycophant.” (American Heritage® Dictionary of the English Language, Fifth Edition. Copyright © 2016 by Houghton Mifflin Harcourt Publishing Company. Published by Houghton Mifflin Harcourt Publishing Company)

This traditional religious use already carries in it the negative connotation that the term has towed throughout its history until today. But this was non-medical history; it is likely that not many people knew the term and used it in everyday language.

Are the roots of placebo all British?

The term entered medical history in the late 18th century, with a few British doctors that can claim to be the originator (1): For one, there is Alex Sutherland (born before 1730 – died after 1773) a doctor living and practicing in Bath, Summerset, who used the term to describe a certain type of doctors keen to prescribe fashionable medicines such as waters with healing power, which he called “placebo” (doctors) in a popular book published in 1763 (2). About the same time, William Cullen (1710 – 1790) from Edinburgh, Scotland, used it for the first time in a textbook, his Clinical Lectures (3): He gave a patient mustard powder as a remedy noting “… that I did not trust much to it, but I gave it because it is necessary to give a medicine, and as what I call a placebo,” summarizing today’s entire discussion in a single sentence: Placebos are to please the patient and improve symptoms because of that – what we call the placebo effect. And the third gentleman is John Coakley Lettsom (1744-1815), a doctor from London who resumed a similar position to Cullen; they used placebos of ineffective doses of what were popular medicines of their time (1).

It is not presumable that these textbooks were known and read by many practicing physicians, either in England or abroad, neither in their time nor today, but the spread of the word (and the meaning) is illustrated by an interesting, very recent paper: The British Medical Journal (BMJ), one of the oldest medical journals in the western world, publishing weekly since 1840. After BMJ had digitized its entire archive, it was possible to back-search the volumes from January 1840 to December 1899 (60 years, equalling a total of 3000 weekly issues, or more than 50,000 articles) for the term “placebo” and its meaning. This screening brought about only 71 citations (4) — on average 1 per year — but with increasing frequency.

Not the term, but the idea was present elsewhere, e.g. in Germany

Even Samuel Hahnemann (1755 – 1843), inventor of homeopathy and an early promoter of complementary and alternative medicine, was quite aware of the placebo effect, but he did not mean his homeopathic remedies. Thanks to Robert Jütte, a medical historian at the Robert Bosch Institute in Stuttgart, Germany, we know about Hahnemann´s placebo use (5): For many decades, Hahnemann kept casebooks in which he documented patients he had treated and how he treated them. And he noted, quite similarly to Cullen, “In the meantime, until the second medicament is given, one can soothe the patient’s mind and desire for medicine with something inconspicuous such as a few teaspoons a day of raspberry juice or sugar of milk” (Hahnemann 1814, according to (5), p 210). In his casebooks, Hahnemann noted a “§” sign in case he had – in his opinion – prescribed such a placebo, and Jütte (5) found that in some years, e.g. 1833 to 1835, more than 50% of his prescriptions were of this kind, in some (1821) even higher – not counting the homeopathic prescriptions, but that is a different story. One wonders whether Hahnemann knew the term at all, unless he was a regular reader of BMJ.

It is of some interest (and some irony as well) that the contemporary critiques of Hahnemann – during his lifetime – were so much concerned about homeopathy influencing patients’ doctor selection and medical compliance, that they set out to perform the first randomized placebo-controlled trial to test the efficacy of homeopathy, again without using (and presumably even knowing) the term placebo, in 1835 (6). We know about the “table salt experiments” (Kochsalzversuche) in Nuremberg, Germany, from a small booklet published in 1835 (7). The author reports from a “society of truth-loving men” that assembled to prove or disapprove the efficacy of homeopathy; it is certainly one of the oldest and earliest randomized placebo-controlled trials in medical history. As a side-note, a similar trial of homeopathy had been performed in St. Peterburg, Russia, some years before (1829 and 1834) with a negative outcome, which left homeopathy banned in Russia for some time (8).

A placebo-controlled trial as early as 1835

The trial was generated by a bet between a conventionally-treating local physician (called Dr. Truehold/Wahrhold, a pseudonym for Dr. Friedrich Wilhelm von Hoven, a reputable physician and academic of his time) and his homeopathic counterpart, the only homeopathic doctor in Nuremberg at this time, Dr. Reuter. They had delivered a public battle of words (9, 10), during which Dr. Reuter suggested that his counterpart should take 100 drops of a homeopathic remedy (dissolved sodium salt at a concentration of one decillion = 1/1060, a high “potentiation” in homeopathic terms) and should observe his symptoms subsequently for a few days; according to Hahnemann’s doctrine, this should induce cholera-like symptoms. In fact, Dr. Reuter suggested an entire protocol for a proper study to show that homeopathy does work.

Dr. Truehold and five of his friends produced the respective solutions according to Hahnemann’s recipe and tested it among themselves, without many results. They then provided family members and friends with the “drug,” again without any results. They finally decided to conduct a larger trial (following Dr. Reuter’s suggested design), for which they recruited members of the community through advertisements in local newspapers. Since Dr. Reuter refused to prepare the homeopathic solution himself, the local pharmacist and two of his helpers were recruited to produce the remedy, and a commission was established from local notabilities (partly members of the city council) to supervise the whole procedure and to summarize the minutes of the test. The commission finally established and consented a procedure to follow for production of the drug/placebo.

More than 120 community members of all social classes (clerks men, handymen, academics, inn-keepers, actors, artists, merchants, doctors, military people etc.) responded and assembled in the ballroom of a local inn, the Red Cock, on Thursday, February 19th, 1835 (the original mistakenly said it to be a Friday); of them, 48 were willing to take the homeopathic remedy, while the remaining were interested in observing the public procedure (a further 7 volunteers were recruited later). Names and identities of each volunteer were noted upon entry of the room.

Under public supervision, 100 bottles were numbered underneath, thoroughly mixed, and distributed to two tables, where 50 were filled with potentiated saline (sodium salt in the above-cited degree of dissolution in distilled snow water) while another 50 bottles were filled with snow water only. The bottles were then moved to a third table and thoroughly mixed again before distribution to the volunteers. The bottle numbers were added to the list of participants, placed into an envelope, and sealed. Samples of both the homeopathic drug and placebo were sealed and stored as well.

Volunteers were requested to ingest the content of the bottle the next morning without having breakfast and to note whether they experienced unusual or usual symptoms over the next couple of days, to note these, and report it in writing (in signed and sealed envelopes) to the newspaper editorial office (General Newspaper From and For Bavaria, Nuremberg; of the reporting journalist), or to come to the subsequent meeting a month later (March 12th, 1935) to report in person. After all the reports had been noted, the study was unblinded, and the reports were evaluated; 42 reports were available (including 5 of the additionally recruited volunteers), and 13 reports were missing. Accordingly, 19 and 23 participants did not note any unusual symptoms after taking homeopathy and placebo, respectively, while 6 and 3 participants had noted symptoms; of the 13 dropouts, we only know from 4 how they were distributed (2 and 2, resp.), the remaining are not reported, and neither is where the remaining, non-distributed bottles were left.

In light of today’s knowledge of placebo-controlled trials

By today’s standards, the distribution between responders and non-responders (primary outcome) for homeopathy and placebo is not significant (Fisher´s Exact Test, p=.29), but such a test was not performed. While the study is certainly underpowered, the drop-out rate was high (23.6%), the randomization (physical mixing of the bottles) at least questionable (consecutive numbers are sometimes given to people with the same last name = family members), and the blinding may, therefore, not be perfect, the study on the other hand is without doubt an impressive early example of the need and the advantage of a placebo control, even without using the term placebo.

Or, as the head of the commission supervising the trial pointed out in his introductory remarks to the assembled audience on February 19th, 1835: “… since through the eventual probation of such assertions (of homeopathy) science is winning, but also in case not, as some who so far have entrusted the most expensive goods on earth, health and life, to known homeopathic art of healing, may be made more careful and then in case deadly disease processes need to be turned away with firm hands, searches help from science …” ((7), page 12).

This is part 14 of a series covering “placebo” provided by Paul Enck and Sibylle Klosterhalfen from the Tübingen University Hospital. Continuous updates on placebo research can be found at www.jips.online.

References:

1. Jutte R. The early history of the placebo. Complementary therapies in medicine. 2013;21(2):94-7.
2. Sutherland A. Attempts to revive Ancient Medical Doctrines. London: A.Millard; 1763.
3. Kerr CE, Milne I, Kaptchuk TJ. William Cullen and a missing mind-body link in the early history of placebos. Journal of the Royal Society of Medicine. 2008;101(2):89-92.
4. Raicek JE, Stone BH, Kaptchuk TJ. Placebos in 19th century medicine: a quantitative analysis of the BMJ. Bmj. 2012;345:e8326.
5. Jutte R. Hahnemann and placebo. Homeopathy: the journal of the Faculty of Homeopathy. 2014;103(3):208-12.
6. Stolberg M. Inventing the randomized double-blind trial: the Nuremberg salt test of 1835. Journal of the Royal Society of Medicine. 2006;99(12):642-3.
7. Löhner G. Die homöopathischen Kochsalzversuche zu Nürnberg. Nürnberg1835.
8. Dean ME. ‘An innocent deception’: placebo controls in the St Petersburg homeopathy trial, 1829-1830. Journal of the Royal Society of Medicine. 2006;99(7):375-6.
9. Wahrhold EF. Auch etwas über die Homöopathie. Nürnberg: Johann Adam Stein; 1834.
10. Reuter JJ. Sendschreiben an Dr. E.F.Wahrhold. Nürnberg: Riegel und Wiesner; 1835.