Nocebo response

In the strictest sense, a nocebo response is where a drug-trial's subject's symptoms are worsened by the administration of an inert, sham, or dummy (simulator) treatment, called a placebo.

The original term placebo was a contraction of the term "placebo singer", which denoted an individual who simulated grief at a funeral; and, this, by extension, came to denote any thing that simulated any other thing (thus, A was 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)

By definition, and by stipulation, a placebo is inert. According to current pharmacological knowledge and the current understanding of cause and effect, it contains no chemical (or any other agent) that could possibly cause any of the observed worsening in the subject's symptoms. Thus, any change for the worse must be due to some subject-internal factor.

So, even though the worsening of the subject's symptoms is a direct consequence of their exposure to the placebo, those symptoms have not been chemically generated by the placebo; and because this symptom generation entails a complex of subject-internal activities, we can never speak in terms of simulator-centred nocebo effects, we can only speak of subject-centred nocebo responses.

Although some attribute nocebo responses (or placebo responses) to gullibility, there is no evidence that an individual who manifests a nocebo response (or placebo response) to one treatment will manifest a nocebo response (or placebo response) to another; i.e., there is no fixed nocebo (or placebo) responding trait or propensity.

Also, experiments have shown that no relationship of any sort exists between an individual's measured hypnotic susceptibility and their manifestation of nocebo or placebo responses.

Why a Nocebo Response?
The term nocebo response was coined in 1961 by Walter Kennedy (in fact he actually spoke of a nocebo reaction).

He had observed that another, entirely different and unrelated, and far more recent meaning of the term placebo was emerging into far more common usage in the technical literature (see homonym) ; namely that a "placebo response" (or "placebo reaction") was a "pleasant" response to a real or sham/dummy treatment (this new and entirely different usage was based on the Latin meaning of the word placebo, "I shall please").

Kennedy chose the Latin word nocebo (meaning "I shall harm", on the basis that it was the opposite of placebo's "I shall please") to denote the placebo response's counterpart, an "unpleasant" response to the application of real or sham treatment.

Kennedy very strongly emphasized that his specific usage of the term nocebo did not refer to "the iatrogenic action of drugs" (see iatrogenesis) -- in other words, according to Kennedy, there was no such thing as a nocebo effect, there was only a nocebo response.

He insisted that a nocebo reaction was subject-centred, and he was emphatic that the term nocebo reaction specifically referred to "to a quality inherent in the patient rather than in the remedy".

Even more significantly, Kennedy also stated that whilst "nocebo reactions do occur [they should never be confused] with true pharmaceutical effects, such as the ringing in the ears caused by quinine".

This is strong, clear and very persuasive evidence that Kennedy was precisely speaking of an outcome that had been totally generated by a subject's negative expectation of a drug or ritual's administration; which was the exact counterpart of a placebo response generated by a subject's positive expectation.

And, finally, and most definitely, Kennedy was not speaking of an active drug's unwanted, but pharmacologically predictable negative side-effects (something for which the term nocebo is being increasingly used in current literature).

Ambiguity of Medical Usage
In an important recent paper, Stewart-Williams and Podd argue that using the contrasting terms placebo and nocebo to label inert agents that produce pleasant, health-improving or desirable outcomes, or to label unpleasant, health-diminishing, or undesirable outcomes respectively, is extremely counterproductive.

For example, precisely the same inert agents can produce analgesia and hyperalgesia -- the first of which, from this definition, would be a placebo, and the second a nocebo.

A second problem is that precisely the same effect, such as immunosuppression, may be quite desirable for a particular subject with an autoimmune disorder but be quite undesirable for most other subjects. Thus, in the first case, the effect would be a placebo, and in the second, a nocebo.

A third problem is that the prescriber would not know whether the relevant subjects had actually considered the effects they experienced to be subjectively desirable or undesirable until some time after the drugs had been administered.

A fourth problem is that, in cases such as this, precisely the same phenomena are being generated in all of the subjects, and these are being generated by precisely the same drug, which is acting in all of the subjects through precisely the same mechanism. Yet, just because the phenomena in question have been subjectively considered to be desirable to one group, but not the other, the phenomena are now being labelled in two mutually exclusive ways (i.e., placebo and nocebo); and this is giving the false impression that the drug in question has produced two entirely different phemnomena.

These sorts of argument produce a strong case that -- despite the fact that, in some of its applications, the term placebo denotes some thing that pleases (compared with it denoting an inert sumulator) -- the desirability (placeboic nature) or undesirability (noceboic nature) of the phenomena that have been manifested by a subject subsequent to a drug's administration should never be part of the definition of what constitutes either a placebo or a placebo response.

Ambiguity of Anthropological Usage
It is self-evident that belief kills (e.g., "voodoo death") and belief heals (e.g., faith healing).

Certain anthropologists, such as Robert Hahn and Arthur Kleinman have attempted to extend the placebo/nocebo distinction into another realm: that of the rituals performed in order to heal (placebo rituals) and those performed in order to harm (nocebo rituals).

As the meaning of the two inter-related terms has extended, we now find anthropologists speaking of nocebo or placebo (harmful or helpful) rituals, that entail nocebo or placebo (unpleasant or pleasant) procedures, about which subjects can have nocebo or placebo ((harmful or beneficial) beliefs, that are delivered by operators that can have nocebo or placebo (pathogenic/disease-generating or salutogenic/health-promoting) expectations, that are delivered to subjects that can have nocebo or placebo (negative/fearful/despairing or positive/hopeful/confident) expectations about the ritual itself, which are delivered by operators with nocebo or placebo (malevolent or benevolent) intentions, in the hope that the rituals will generate nocebo or placebo (injurious/harmful or curative/healthy) outcomes; and, that all of this depends upon the operator's overall beliefs in the harmful nature of the nocebo ritual or the the beneficial nature of the placebo ritual.

Yet, it may be even more complex; for, as Hahn and Kleinman indicate, there can be paradoxical placebo outcomes from nocebo rituals,and paradoxical placebo outcomes from nocebo rituals (see also unintended consequences).