Placebo (origins of technical term)

The technical term placebo is precisely applied in the specialized medical domains of pharmacology, nosology, and aetiology to denote the pharmacologically inert, dummy simulator of an "active" drug that serves as a scientific control in clinical trials designed to determine the clinical efficacy of that particular drug.

In particular, these clinical trials are conducted in order to determine whether a drug's supposedly active ingredients affect the subject through direct physiochemical processes or through mind-mediation.


 * Whether the object of your faith be real or false, you will nevertheless obtain the same effects. Paracelsus (1490-1541)

Inertness
Although placebos are generally characterized as pharmacologically inert substances, sham treatments, or inactive procedures, they are only inert, sham, or inactive in the particular sense that they have no known cause and effect relationship with any of the pre-designated, biochemical, physiological, behavioural, emotional and/or cognitive outcomes of the pharmacologically active and known-to-be-efficacious intervention that might have otherwise been applied.

They are, however, not inert, sham, or inactive in any other manner of speaking; and they may well, in and of themselves, generate considerable change within any given subject, at any given time, under any given circumstances.
 * Actually the question of inert versus active placebo is academic, because there is no such thing as an inactive substance. For example, distilled water injections can cause hemolysis and water intoxication. Ingestion of two 5-grain [325 mg] capsules of sacchari lactis [ milk sugar ], QID [quater in die, "four times a day"], for 30 years, can result in a weight gain of 30 pounds, so that even sugar can hardly be considered harmless, indifferent, or inert. (Shapiro, 1968, p.675)

Applications of the term placebo
Whilst it is universally accepted that the Latin word placebo means "I shall please", the precise meaning of the English technical term placebo is not always immediately clear.

In the strictest sense, the technical term placebo denotes the inert, dummy simulator of an "active" drug that serves as a control in the clinical trials of drug efficacy, that are conducted to determine whether a drug's supposedly active ingredients affect its recipients through direct physiochemical processes or through mind-mediation.

However, some such as Gaddum (1954, p.197) have taken the position that -- by contrast with the "counterfeit objects" that are genuinely "dummy drugs" (which "cannot be distinguished from the real treatment" and are "indistinguishable in appearance, taste and smell from the real [drugs]" and, by definition, "have no effect", and "are sometimes called placebos" -- only those "counterfeit objects" that really do have some biochemical, physiological, behavioural, emotional and/or cognitive effect on a subject, and produce that effect through a psychological (rather than pharmacological) mechanism, can truly be called placebos.
 * A placebo is something which is intended to act through a psychological mechanism. It is an aid to therapeutic suggestion, but the effect which it produces may be either psychological or physical. It may make the patient feel better without any obvious justification, or it may produce actual changes in such things as gastric secretion. Dummy tablets may, of course, act as placebos, but, if they do, they lose some of their value as dummy [control] tablets. They have two real functions, one of which is to distinguish pharmacological effects from the effects of suggestion, and the other is to obtain an unbiased assessment of the result of the experiment. (p.197)

In a far more general sense, the term placebo is also sometimes used to denote the pharmacologically inert, but subjectively soothing "sugar pill", electuary, or pharmaceutical syrup that a doctor might give a patient in order to gratify their need for treatment.

The term placebo may also be used pejoratively to mean a treatment or remedy that has no demonstrated efficacy whatsoever; and it is most often used to describe earlier forms of treatment to which some level of therapeutic efficacy had once been actively misattributed.

In everyday English, the word placebo is also used to denote a pharmacologically active drug, treatment or surgical procedure that has a positive, beneficial, desirable or pleasant outcome. The negative counterpart of this sort of placebo -- an active drug, treatment or procedure that has an injurious, undesirable or unpleasant outcome -- is called a nocebo.


 * …a therapy may be used with or without knowledge that it is a placebo. It would include treatments given in the belief that they were not placebos, but which actually are placebos by objective evaluation. The placebo may be inert or active and may include, therefore, all medical treatment no matter how potentially specific or how administered. It may take the form of oral and parenteral medication, topical preparations, inhalants, and all mechanical, surgical, psychotherapeutic, and other therapeutic techniques. It would include a treatment that produced symptoms or side effects which were not specific for that treatment. A placebo may or may not result in a placebo effect, and the effect may be favorable or unfavorable — that is, positive or negative.

In the absence of contextual evidence -- and, in particular, in the absence of any direct knowledge of the theoretical orientation of the individual who is using the term -- it may be quite impossible to accurately and unequivocally identify its meaning in a particular case, due to the extremely wide range of different (and possibly mutually exclusive) meanings to which the term may be applied.

Homonymy vs. polysemy
This confusion and ambiguity within the term's application, to a large extent is due to the complex nature of the English word. For, rather than there being an extended range of linked polysemous meanings of a single term (i.e., placebo) that have multiplied, over time, from a single original source, many of the applications of the term placebo emanate from quite different sources.

Consequently, the range of different usages of the term placebo are homonymous (rather than polysemous) usages; with significantly different concepts sharing the same spelling (as with the homonyms ear, bank, sound, corn, and scale).

Origins of placebo (the simulator)
By the 8th century the Roman Catholic Church had established the final form and content of its Office of the Dead ritual.

This ceremony was designed to bring solace to the living just as much as comfort to the dead. As oart of the ritual, the celebrant would recite certain extended passages from scripture (mainly from the Psalms). At the end of each recited passage, the congregation would make a specific response (antiphon) to each recitation. The celebrant’s first recitation was Psalm 116:1-9 -- or, Psalm 114:1-9 in Septuagint version -- and the congregation’s first responding antiphon was verse 9 of that Psalm.

The Roman Catholic Church had chosen Jerome’s first (circa 384) Greek-to-Latin version of the Vulgate as the source of the celebrant’s text, rather than his third (circa 405) Hebrew-to-Latin version.

The Psalms in his first version were translated directly into Latin from the Septuagint’s Greek text. The Psalms in his third version had been translated directly from the Hebrew text of his day into Latin.

There is a significant difference in the Septuagint Psalm’s 114:9’s Latin translation, "placebo Domino in regione vivorum" ("I will please the Lord in the land of the living"), and the Hebrew Psalm's 116:9’s Latin translation, "ambulabo coram Domino in regione vivorum" ("I will walk before the Lord in the land of the living" -- which also matches the English of the King James Version ) and the English version of the Islamic Zabur 116:9.

In France, it was the custom for the mourning family to distribute largesse to the congregation immediately following the Office of the Dead ritual. As a consequence, distant relatives and other unrelated parasites would attend the ceremony, simulating great anguish and grief -- in the hope of, at least, being given a meal and something to drink.

This practice was so widespread that these parasites were soon recognized as the personification of all things useless; and were considered to be archetypical simulators. Because the grief simulators' first collective act was to chant "placebo Domino in regione vivorum" they were collectively labelled (in French) as either "Placebo Singers" or "Singers of Placebo"; and they were so labelled because they sang the word "placebo", not because they were "choral placaters", using their song to please.

In the light of all of the subsequent terminological confusion it is significant that, if Jerome’s third version of the Vulgate had been selected for the ritual’s text instead of the first -- or if the Septuagint’s translators had translated an entirely different Hebrew text -- the congregation’s first response would have been "ambulabo coram Domino in regione vivorum". As a consequence, the simulators would have been "Ambulabo Singers" or "Singers of Ambulabo".

By the time of Chaucer’s Canterbury Tales (circa 1386), the disparaging English expression placebo-singer, meaning a parasite or a sycophant, was well established in the English language.

The English word placebo also denoted a sycophant, and it was this application of the word placebo that seems to have oriented those unaware of the term’s origins, over time, to the irrelevant fact that the Latin word placebo means "I shall please".

However, the first English meaning of "placebo" is simulator; and it denotes any thing that simulates any other thing (thus, A is a placebo, or simulator of B).


 * …for Distinction Sake, a Deceiving by Words, is commonly called a Lye, and a Deceiving by Actions, Gestures, or Behavior, is called Simulation… Robert South (1643-1716)

South was speaking of the differences between a falsehood and an honestly mistaken statement. The difference being that, in order for the statement to be a lie, the truth must be known -- and the opposite of that truth must have been knowingly uttered -- and, from this, to the extent to which a lie involves uttering deceptive words, a simulation involves the performance of deceptive actions, deceptive gestures, or deceptive behavior.

Thus, if a simulation is genuinely false, the real truth must be known in order for some other thing (i.e., other than the truth) to be presented in its stead; otherwise, one would not know what to offer up in simulation.

Origins of placebo (the morale-booster)
Hooper’s (1811) Quincy’s Lexicon-Medicum defines placebo as "an epithet given to any medicine adapted more to please than benefit the patient".

In the practice of medicine it had been long understood that, as Ambroise Paré (1510–1590) had expressed it, the physician’s duty was to "cure occasionally, relieve often, console always".

According to Jewson, eighteenth century English medicine was gradually moving away from the patient having a considerable interaction with the physician; and, through this consultative relationship, having an equal influence on the construction of the physician’s therapeutic approach.

It was gradually moving towards that of the patient being the recipient of a far more standard form of intervention that was determined by the prevailing opinions of the medical profession of the day. Jewson characterizes this as parallel to the changes that were taking place in the manner in which medical knowledge was being produced; namely a transition all the way from "bedside medicine", through "hospital medicine", to "laboratory medicine".

From this point of view, the last vestiges of the consoling approach to treatment are to be found in the administration -- often without any sort of adequate history being taken, or any sort of appropriate physical examination being made -- of the morale-boosting and pleasing remedies, such as the "sugar pill", electuary or pharmaceutical syrup; all of which had no known pharmacodynamic action.

Those doctors who provided their patients with these sorts of morale-boosting therapies -- which, whilst having no pharmacologically active ingredients, provided reassurance and comfort  -- did so either to reassure their patients whilst the vis medicatrix naturæ (i.e., "the healing power of nature") performed its normalizing task of restoring them to health, or to gratify their patients’ need for an active treatment.
 * To argue with a man, and especially with a woman, that there is little the matter with them might be thought injudicious, and to advise them to return at a more convenient occasion requires more time and resolution than writing out a prescription or administering a placebo. (Steele, 1891)

By contrast, Shapiro (1968) reports that many of his respondents expressed the opinion that, in cases such as these, it was wrong to think of the medication as inert:
 * If a placebo is prescribed by a physician because it is thought that it will help the patient, then it is a specific [remedy] and therefore not a placebo [at all].

An editorial in the British Medical Journal of 19 January 1952 warns that any failure of the placebo to affect the disorder for which the patient has presented for treatment may only serve to reinforce the patient's belief that they have a serious disease:
 * But it is a fallacy to suppose that an inactive medicine can do no harm. If prescribed in a perfunctory way for a patient needing explanation and reassurance it may increase faith in his disease rather than in the remedy, and a doctor who gives a placebo in the wrong spirit may harm the patient. (Anon, 1952, p.150)

More than sixty years ago, Pepper noted the significant fact that "there may be a time when during the carrying out of diagnostic tests it is undesirable to give potent medicine lest it interfere with the tests and yet the patient must be encouraged by treatment" (1945, p.411). He had this to say about the application of placebos in routine medical practice:


 * …there is a certain amount of skill in the choice and administration of a placebo. In the first place, it must be nothing more than what the name implies a medicine without any pharmacologic action whatever. Even a mild sedative is not a true placebo. Secondly, its name must be unknown to even the most inveterate patient who knows most drugs by name and is always quick to read the prescription. If the medicines named are familiar the type of patient who needs a placebo will promptly exclaim that this or that drug had been tried and "had not helped me" or "had upset my stomach". It is well if the drug have a Latin and polysyllabic name; it is wise if it be prescribed with some assurance and emphasis for psychotherapeutic effect. The older physicians each had his favorite placeboic prescriptions -- one chose Tincture of Condurango, another the Fluidextract [sic] of Cimificuga nigra. Certainly this latter by its Latin name might be expected to have more supratentorial action than if one merely wrote for the Black Cohosh, and Condurango would be more efficacious than sugar of milk.

Origins of placebo (the useless)
"Heroic medicine" had begun to fall from favour long before research scientists such as Robert Koch, Louis Pasteur, Frederick Hopkins and Casimir Funk demonstrated that the presence or the absence of specific agents could cause specific diseases, and long before the chemical laboratory orientation of Abraham Flexner’s 1910 Flexner Report had evolved into the evidence-based medicine of the 1970s.

As the earliest precursors of modern, scientific, conventional medicine began to emerge, medical scholars began to routinely question:
 * the principles of their medical diagnosis and prognosis,
 * the efficacy of their conventional medical practices,
 * the correctness of their current anatomical, physiological and neurological knowledge, and
 * the true scientific status of the drugs and therapies in their pharmacopoeia.

In many cases, active agents were identified within supposedly efficacious treatments; such as salicylic acid within decoctions of willow bark, which eventually led to the production of the drug aspirin.

However, it was also apparent that certain other treatments, such as the treatment of syphilis with salves made from mercury, had no efficacy whatsoever; and, regardless of the level of their acceptance within the medical profession, or the curative intentions associated with their administration, they were medically useless.

It was these sorts of useless decoctions, drugs, treatments, remedies and procedures that were given the pejorative label placebo -- the second edition of Motherby’s (1785) New Medical Dictionary defines placebo as "a common place method or medicine".

Because this usage does not appear in English -- or in any English, French, German, Italian, or Portuguese dictionary -- prior to Motherby’s 1785 edition, Shapiro (1968, pp.656-657) is certain that this pejorative use of placebo was actually coined by Motherby.

Origins of placebo (the simulator in a clinical trial)
The aim of a clinical trial is to determine what treatments, delivered in what circumstances, to which patients, in what conditions, are the most efficacious; as well to obtain objective evidence of what treatments are efficacious and specific (i.e., rather than just being efficacious), or are intentionally efficacious and specific (i.e., rather than being just intentionally efficacious or inadvertently efficacious)

In pursuit of these goals, the question “Who does what, with which, and to whom?” is central to task of identifying what are: specific effects (those for which the treatment was administered), non-specific effects (predictable "side-effects"), unintended effects (i.e., the placebo responses), or simply serendipitous effects of treatment (i.e., effects of the subject just being "in therapy").

In 1747, James Lind (1716-1794), the Naval Surgeon on HMAS Salisbury, conducted what was most likely the first-ever clinical trial when he investigated the efficacy of citrus fruit in cases of scurvy.

He randomly divided twelve scurvy patients, whose "cases were as similar as I could have them", into six pairs. Each pair was given a different remedy. He noted that the pair who had been given the citrus were so restored to health within six days of treatment that one of them returned to duty, and the other was well enough to attend the rest of the sick. Lind’s approach can still be seen in the way that the comparative efficacy of various treatments for particular sorts of cancer are determined, by examining and comparing the five year survival rates of those who have been treated with each of the different interventions.

In 1784, the French Royal Commission into the existence of animal magnetism investigated the practices of Charles d’Eslon (1739-1786); and compared the effects of his allegedly magnetized water with that of plain water.

In 1799, John Haygarth investigated the efficacy of Perkins tractors -- they were called "tractors" because they were drawn across the skin -- by comparing the results from dummy wooden tractors with a set of allegedly "active" metal tractors.

It was not until 1863 that Austin Flint (1812–1886) conducted the first-ever trial that directly compared the efficacy of a dummy simulator with that of an active treatment. This was a significant departure from the (then) customary practice of contrasting the consequences of an active treatment with what Flint described as "the natural history of [an untreated] disease".

Flint’s paper is the first time that either of the terms "placebo" or "placeboic remedy" were ever used to refer to a dummy simulator in a clinical trial.
 * …to secure the moral effect of a remedy given specially for the disease, the patients were placed on the use of a placebo which consisted, in nearly all of the cases, of the tincture of quassia, very largely diluted. This was given regularly, and became well known in my wards as the placeboic remedy for rheumatism.

Ambiguity of medical usage
See Nocebo

Ambiguity of anthropological usage
See Nocebo