Nocebo

In medicine, a nocebo (Latin for "I shall harm") is a harmless substance that creates harmful effects in a patient who takes it. The nocebo effect is the negative reaction experienced by a patient who receives a nocebo. Conversely, a placebo is an inert substance that creates either a positive response or no response in a patient who takes it. The phenomenon in which a placebo creates a positive response in the patient to which it is administered is called the placebo effect. The nocebo effect is less well-studied and well-known, by both scientists and the public, than the placebo effect.

Both nocebo and placebo effects are entirely psychogenic. Rather than being caused by a biologically active compound in the placebo itself, these reactions result from a patient's expectations about how the substance will affect him or her. Though they originate exclusively from psychological sources, nocebo effects can be either psychological or physiological.

Etymology
The term nocebo (Latin nocēbō, "I shall harm", from noceō, "I harm") was chosen by Walter Kennedy, in 1961, to denote the counterpart of one of the more recent applications of the term placebo (Latin placēbō, "I shall please", from placeō, "I please"); namely, that of a placebo being a drug that produced a beneficial, healthy, pleasant, or desirable consequence in a subject, as a direct result of that subject's beliefs and expectations.

Description
W.R. Houston may have been the first to have spoken of a doctor's deliberate application of harmful "placebo" procedures, as distinct from the other, harmless sort of "placebo" procedures a doctor might apply and whose "usefulness was in direct proportion to the faith that the doctor had and the faith that he was able to inspire in his patients." Houston (1938, p. 1418) wrote: "... [and while the efficacy of the placebo procedure] is believed in by the doctor, [the placebo procedure itself] is no longer harmless but harmful, sometimes very dangerous. It would seem peculiarly contradictory to speak of the painful and dangerous placebo, yet men are so constituted that they feel the need in dire extremity of resorting to dread measures. Nervous patients in particular, feel that a certain standing and sanction is bestowed upon their maladies when violent therapeutic measures are used."

Houston spoke of three significantly different categories of placebo (pp.1417-1418):
 * the drug that the physician knows to be inert, but which the subject believes to be potent;
 * the drug which is believed to be potent by both subject and physician, but which later investigation proves to have been totally inert;
 * the drug which is believed to be impotent by both subject and physician, but is actually harmful and dangerous, rather than being inert and harmless.

The term "nocebo response" originally meant only an unpredictable and unintentional belief-generated injurious response to an inert procedure, but there is an emerging practice of labelling drugs that produce unpleasant consequences as "nocebo drugs" meaning that the term "nocebo response" may be used to label an intentional, entirely pharmacologically-generated and quite predictably injurious outcome that has ensued from the administration of an active (nocebo) drug.

Anthropologists use the term "nocebo ritual" to describe a procedure, treatment, or ritual that has been performed (or a herbal remedy or medication that has been administered) with malicious intent, by contrast with a placebo procedure or treatment or ritual that is performed with a benevolent intent.

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

According to current pharmacological knowledge and the current understanding of cause and effect, a placebo 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.

Negative expectations can also cause analgesic effects of anesthetic medications to be abolished.

The worsening of the subject's symptoms or elimination of positive effects is a direct consequence of their exposure to the placebo, but those symptoms have not been chemically generated by the placebo. Because this generation of symptoms entails a complex of "subject-internal" activities, in the strictest sense, we can never speak in terms of simulator-centred "nocebo effects," but only in terms of subject-centred "nocebo responses."

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

McGlashan, Evans & Orne (1969, p. 319) found no evidence of what they termed a "placebo personality." Also, in a carefully designed study, Lasagna, Mosteller, von Felsinger and Beecher (1954), found that there was no way that any observer could determine, by testing or by interview, which subject would manifest a placebo reaction and which would not.

Experiments have shown that no relationship exists between an individual's measured hypnotic susceptibility and his/her manifestation of nocebo or placebo responses.

Causes
The term "nocebo response" was coined in 1961 by Walter Kennedy (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 ("I shall harm") because it was the opposite of the Latin word "placebo", and used it to denote the counterpart of the placebo response: namely, 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": 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 "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 that would have been 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 a 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 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 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 does not know whether the relevant subjects consider the effects that they experience to be subjectively desirable or undesirable until some time after the drugs have actually 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 phenomena.

These sorts of argument produce a strong case that – despite the fact that, in some of its applications, the term "placebo" is used to denote something that pleases (compared with it denoting an inert simulator) – the desirability (placeboic nature) or undesirability (noceboic nature) of the phenomena that have been manifested by a subject, after a drug has been administered, should never be part of the definition of what constitutes either "a placebo" or "a placebo response".

Ambiguity of anthropological usage
Some people maintain that belief kills (e.g., "voodoo death": Cannon (1942) describes a number of "voodoo deaths" from a variety of different cultures) and belief heals (e.g., faith healing).

A "self-willed" death (due to voodoo hex, evil eye, pointing the bone procedure, etc.) is an extreme form of a culture-specific syndrome or mass psychogenic illness that produces a particular form of psychosomatic or psychophysiological disorder which results in a psychogenic death.


 * Rubel (1964) spoke of "culture bound" syndromes, which were those "from which members of a particular group claim to suffer and for which their culture provides an etiology, diagnosis, preventive measures, and regimens of healing” (p.268).

It is important to distinguish these "self-willed deaths" from other "self-imposed" sorts of death, such as:
 * the "self-inflicted deaths" of suicide, voluntary euthanasia, or the refusal of life-extending treatment;
 * the "heroic" "self-inflicted death" of a soldier who throws himself on a hand grenade to save his mates, or that of the Antarctic explorer Captain Lawrence Oates ("I am just going outside and may be some time"); or
 * the "religious self-inflicted death"' of the self-immolating suttee, or the mors voluntaria religiosa (= "voluntary religious death") of the aged person, whom religious elders have permitted to voluntarily, peacefully, and slowly die by fasting.

Certain anthropologists, such as Robert Hahn and Arthur Kleinman, have extended the placebo/nocebo distinction into this realm in order to allow a distinction to be made between rituals, like faith healing, that are performed in order to heal, cure, or bring benefit (placebo rituals) and others, like "pointing the bone", that are performed in order to kill, injure or bring harm (nocebo rituals).

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

Yet, it may become even more terminologically complex; for, as Hahn and Kleinman indicate, there can also be cases where there are paradoxical nocebo outcomes from placebo rituals (e.g. the TGN1412 drug trial ), as well as paradoxical placebo outcomes from nocebo rituals (see also unintended consequences).

Writing from his extensive experience of treating cancer (including more than 1,000 melanoma cases) at Sydney Hospital, Milton (1973) warned of the impact of the delivery of a prognosis, and how many of his patients, upon receiving their prognosis, simply turned their face to the wall and died an extremely premature death: "... there is a small group of patients in whom the realisation of impending death is a blow so terrible that they are quite unable to adjust to it, and they die rapidly before the malignancy seems to have developed enough to cause death. This problem of self-willed death is in some ways analogous to the death produced in primitive peoples by witchcraft ("Pointing the bone")." (p.1435)