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
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
of a medication, they can experience that effect even if the "medication" is actually an inert substance. The complementary concept, the ''
placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures.
In general ...
'' effect, is said to occur when positive expectations improve an outcome. The effect is also said to occur in someone who falls ill owing to the erroneous belief that they were exposed to a toxin, or to a physical phenomenon they believe is harmful, such as EM radiation.
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
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...
.
Etymology and usage
The term ''nocebo'' (
Latin
Latin (, or , ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally a dialect spoken in the lower Tiber area (then known as Latium) around present-day Rome, but through ...
, 'I shall harm', from , 'I harm') was coined by Walter Kennedy in 1961 to denote the counterpart to the use of ''placebo'' (Latin , 'I shall please', from , '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
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequenc ...
such as the
ringing in the ears caused by
quinine
Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to '' Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg ...
. 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.
Response
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
A simulation is the imitation of the operation of a real-world process or system over time. Simulations require the use of models; the model represents the key characteristics or behaviors of the selected system or process, whereas the s ...
) treatment, called a
placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures.
In general ...
. According to current
pharmacological knowledge and the current understanding of
cause and effect
Causality (also referred to as causation, or cause and effect) is influence by which one event, process, state, or object (''a'' ''cause'') contributes to the production of another event, process, state, or object (an ''effect'') where the ca ...
, 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
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
effects of
anesthetic
An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia — in other words, to result in a temporary loss of sensation or awareness. They may be divided into two ...
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
Gullibility is a failure of social intelligence in which a person is easily tricked or manipulated into an ill-advised course of action. It is closely related to credulity, which is the tendency to believe unlikely propositions that are unsupp ...
, 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 found no evidence in 1969 of what they termed a ''placebo personality''. Also, in a carefully designed study, Lasagna, Mosteller, von Felsinger and Beecher in 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
Hypnotic susceptibility measures how easily a person can be hypnotized. Several types of scales are used; however, the most common are the Harvard Group Scale of Hypnotic Susceptibility and the Stanford Hypnotic Susceptibility Scales.
The Harvard ...
and their manifestation of nocebo or placebo responses.
Effects
Side effects of drugs
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
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...
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.
In January 2022, a
systematic review
A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on t ...
and
meta-analysis
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...
concluded that nocebo responses accounted for 72% of adverse effects after the first
COVID-19 vaccine
A COVID19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus that causes coronavirus disease 2019 (COVID19).
Prior to the COVID19 pandemic, an e ...
dose and 52% after the second dose.
Electromagnetic hypersensitivity
Evidence suggests that the symptoms of
electromagnetic hypersensitivity are caused by the nocebo effect.
Pain
Verbal suggestion can cause
hyperalgesia (increased sensitivity to pain) and
allodynia
Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, bad sunburn can cause temporary allodynia, and touching sunburned skin, or running cold or warm water over it, can be very painful. It i ...
(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.
Ambiguity of medical usage
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
Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professional ...
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
Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...
, may be desirable for a subject with an
autoimmune disorder
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly ...
, 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
A phenomenon ( : phenomena) is an observable event. The term came into its modern philosophical usage through Immanuel Kant, who contrasted it with the noumenon, which ''cannot'' be directly observed. Kant was heavily influenced by Gottfried ...
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
In logic and probability theory, two events (or propositions) are mutually exclusive or disjoint if they cannot both occur at the same time. A clear example is the set of outcomes of a single coin toss, which can result in either heads or tails ...
ways (i.e., placebo and nocebo); and this is giving the false impression that the drug in question has produced two different phenomena.
Ambiguity of anthropological usage
Some people maintain that belief kills (e.g.,
voodoo death: Cannon in 1942 describes a number of instances from a variety of different cultures) and belief heals (e.g.,
faith healing
Faith healing is the practice of prayer and gestures (such as laying on of hands) that are believed by some to elicit divine intervention in spiritual and physical healing, especially the Christian practice. Believers assert that the healin ...
). A self-willed death (due to voodoo
hex,
evil eye
The Evil Eye ( grc, ὀφθαλμὸς βάσκανος; grc-koi, ὀφθαλμὸς πονηρός; el, (κακό) μάτι; he, עַיִן הָרָע, ; Romanian: ''Deochi''; it, malocchio; es, mal de ojo; pt, mau-olhado, olho gordo; ar ...
,
pointing the bone procedure, etc.) is an extreme form of a
culture-specific syndrome
In medicine and medical anthropology, a culture-bound syndrome, culture-specific syndrome, or folk illness is a combination of psychiatric and somatic symptoms that are considered to be a recognizable disease only within a specific society or c ...
or
mass psychogenic illness
Mass psychogenic illness (MPI), also called mass sociogenic illness, mass psychogenic disorder, epidemic hysteria, or mass hysteria, involves the spread of illness symptoms through a population where there is no infectious agent responsible for c ...
that produces a particular form of
psychosomatic
A somatic symptom disorder, formerly known as a somatoform disorder,(2013) dsm5.org. Retrieved April 8, 2014. is any mental disorder that manifests as physical symptoms that suggest illness or injury, but cannot be explained fully by a general ...
or
psychophysiological
Psychophysiology (from Greek , ''psȳkhē'', "breath, life, soul"; , ''physis'', "nature, origin"; and , ''-logia'') is the branch of psychology that is concerned with the physiological bases of psychological processes. While psychophysiology ...
disorder which results in a psychogenic death. Rubel in 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:
* 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; 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.
Yet it may become even more terminologically complex, for as Hahn and Kleinman indicate, there can also be cases where there are
paradoxical
A paradox is a logically self-contradictory statement or a statement that runs contrary to one's expectation. It is a statement that, despite apparently valid reasoning from true premises, leads to a seemingly self-contradictory or a logically u ...
nocebo outcomes from placebo rituals, as well as paradoxical placebo outcomes from nocebo rituals (see also
unintended consequence
In the social sciences, unintended consequences (sometimes unanticipated consequences or unforeseen consequences) are outcomes of a purposeful action that are not intended or foreseen. The term was popularised in the twentieth century by Ameri ...
s). Writing from his extensive experience of treating cancer (including more than 1,000
melanoma
Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
cases) at
Sydney Hospital
Sydney Hospital is a major hospital in Australia, located on Macquarie Street in the Sydney central business district. It is the oldest hospital in Australia, dating back to 1788, and has been at its current location since 1811. It first rece ...
, Milton in 1973 warned of the impact of the delivery of a
prognosis
Prognosis ( Greek: πρόγνωσις "fore-knowing, foreseeing") is a medical term for predicting the likely or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) or remain sta ...
, 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
Malignancy () is the tendency of a medical condition to become progressively worse.
Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...
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')".
Ethics
A number of researchers have pointed out that the harm caused by communicating with patients about potential treatment
adverse events raises an ethical issue. In order to respect
autonomy
In developmental psychology and moral, political, and bioethical philosophy, autonomy, from , ''autonomos'', from αὐτο- ''auto-'' "self" and νόμος ''nomos'', "law", hence when combined understood to mean "one who gives oneself one' ...
, one is required to inform a patient about what harms a treatment is likely to cause. Yet the way in which potential harms are communicated could cause additional harm, which may violate the ethical principle of
non-maleficence
' () is a Latin phrase that means "first, do no harm". The phrase is sometimes recorded as '.
Non-maleficence, which is derived from the maxim, is one of the principal precepts of bioethics that all students in healthcare are taught in school a ...
. It may be possible that nocebo effects can be reduced while respecting autonomy using different models of
informed consent
Informed consent is a principle in medical ethics and medical law, that a patient must have sufficient information and understanding before making decisions about their medical care. Pertinent information may include risks and benefits of treat ...
, including the use of a
framing effect
In the social sciences, framing comprises a set of concepts and theoretical perspectives on how individuals, groups, and societies organize, perceive, and communicate about reality.
Framing can manifest in thought or interpersonal communic ...
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.
See also
Notes
References
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External links
Nocebo and nocebo effectThe Nocebo Effect: Placebo's Evil Twin What modifies a healing response*
ttps://www.science.org/doi/abs/10.1126/scitranslmed.3001244 The Effect of Treatment Expectation on Drug Efficacy: Imaging the Analgesic Benefit of the Opioid RemifentanilThis Video Will Hurt (The Nocebo Effect) via YouTube
BBC Discovery program on the nocebo effectWhat is the Nocebo effect?
{{Authority control
Clinical research
Cultural anthropology
Drug discovery
1960s neologisms
Latin medical words and phrases
Medical terminology
Medicinal chemistry
Mind–body interventions
Somatic psychology