A nocebo effect is said to occur when negative expectations of the patient regarding a treatment cause the treatment to have a more negative effect than it otherwise would have.For example, when a patient anticipates a side effect of a medication, they can suffer that effect even if the "medication" is actually an inert substance. The complementary concept, the placebo effect, is said to occur when positive expectations improve an outcome. Both placebo and nocebo effects are presumably psychogenic, but they can induce measurable changes in the body. One article that reviewed 31 studies on nocebo effects reported a wide range of symptoms that could manifest as nocebo effects including nausea, stomach pains, itching, bloating, depression, sleep problems, loss of appetite, sexual dysfunction and severe hypotension.
The term nocebo (Latin nocēbō , "I shall harm", from noceō , "I harm")was coined by Walter Kennedy in 1961 to denote the counterpart to the use of placebo (Latin placēbō , "I shall please", from placeō , "I please"; a substance that may produce a beneficial, healthful, pleasant, or desirable effect). Kennedy emphasized that his use of the term "nocebo" refers strictly to a subject-centered response, a quality inherent in the patient rather than in the remedy". That is, Kennedy rejected the use of the term for pharmacologically induced negative side effects such as the ringing in the ears caused by quinine. That is not to say that the patient's psychologically induced response may not include physiological effects. For example, an expectation of pain may induce anxiety, which in turn causes the release of cholecystokinin, which facilitates pain transmission.
In the narrowest sense, a nocebo response occurs when a drug-trial 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 subjective factor. Adverse expectations can also cause the analgesic effects of anesthetic medications to disappear.
The worsening of the subject's symptoms or reduction of beneficial 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-centered "nocebo effects", but only in terms of subject-centered "nocebo responses". Although some observers 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 their manifestation of nocebo or placebo responses.
It has been shown that, due to the nocebo effect, warning patients about side effects of drugs can contribute to the causation of such effects, whether the drug is real or not.This effect has been observed in clinical trials: according to a 2013 review, the dropout rate among placebo-treated patients in a meta-analysis of 41 clinical trials of Parkinson's disease treatments was 8.8%. A 2013 review found that nearly 1 out of 20 patients receiving a placebo in clinical trials for depression dropped out due to adverse events, which were believed to have been caused by the nocebo effect. A 2018 review found that half of patients taking placebos in clinical trials report intervention-related adverse events.
Evidence suggests that the symptoms of electromagnetic hypersensitivity are caused by the nocebo effect.
Verbal suggestion can cause hyperalgesia (increased sensitivity to pain) and allodynia (perception of a tactile stimulus as painful) as a result of the nocebo effect.Nocebo hyperalgesia is believed to involve the activation of cholecystokinin receptors.
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 versus 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 the same effect, such as immunosuppression, may be desirable for a subject with an autoimmune disorder, but be 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 desirable or undesirable until some time after the drugs have been administered. A fourth problem is that the same phenomena are being generated in all the subjects, and these are being generated by the same drug, which is acting in all of the subjects through the same mechanism. Yet 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 different phenomena.
Some people maintain that belief kills (e.g., "voodoo death": Cannon (1942) describes a number of instances 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".
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:
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 a premature death: "there is a small group of patients in whom the realization 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')".
A number of researchers have pointed out that the harm caused by communicating with patients about potential treatment adverse events raises an ethical issue. Informing a patient about what harms a treatment is likely to cause is required to respect autonomy. Yet the way in which potential harms are communicated could cause additional harm, which may violate the ethical principle of non-maleficence.It may be possible that nocebo effects can be reduced while respecting autonomy using different models of informed consent, including the use of a framing effect and the authorized concealment. In fact, it has been argued that forcing patients to learn about all potential adverse events against their will could violate autonomy.
A placebo is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets, inert injections, sham surgery, and other procedures.
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An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or procedure, this is called a medical error and not a complication. Adverse effects are sometimes referred to as "iatrogenic" because they are generated by a physician/treatment. Some adverse effects occur only when starting, increasing or discontinuing a treatment. Adverse effects can also be caused by placebo treatments . Using a drug or other medical intervention which is contraindicated may increase the risk of adverse effects. Adverse effects may cause complications of a disease or procedure and negatively affect its prognosis. They may also lead to non-compliance with a treatment regimen. Adverse effects of medical treatment resulted in 142,000 deaths in 2013 up from 94,000 deaths in 1990 globally.
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The word placebo was used in a medicinal context in the late 18th century to describe a "commonplace method or medicine" and in 1811 it was defined as "any medicine adapted more to please than to benefit the patient". Although this definition contained a derogatory implication, it did not necessarily imply that the remedy had no effect.
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Fabrizio Benedetti is professor of physiology and neuroscience at the University of Turin Medical School in Turin, Italy and a researcher in the field of placebo studies. He is known for his research into the placebo and nocebo effects.
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Placebo analgesia occurs when the administration of placebos leads to pain relief. Because placebos by definition lack active ingredients, the effect of placebo analgesia is considered to result from the patient's belief that they are receiving an analgesic drug or other medical intervention. It has been shown that, in some cases, the endogenous opioid system is critical for mediating placebo analgesia, as evidenced by the ability of such analgesia to be reduced by the opioid antagonist naloxone. However, it is also possible for placebo analgesia to be mediated by non-opioid mechanisms, in which case it would not be affected by naloxone. Other research has indicated that the human spinal cord, prefrontal cortex, and rostral anterior cingulate cortex also play a role in placebo analgesia.
Winfried Rief is a German psychologist. Since 2000 he has been a professor of clinical psychology and psychotherapy at the University of Marburg. Rief's research examines the psychological factors involved in the development, maintenance and management of physical complaints, including investigations of somatic symptom disorders and placebo effects. Rief is the founding editor of the academic journal Clinical Psychology in Europe.
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