Nocebo

Walter Kennedy coined the term nocebo (Latin {{Wikt-lang|la|nocēbō}}, "I shall harm", from {{Wikt-lang|la|noceō}}, "I harm"){{cite dictionary|url=http://www.merriam-webster.com/dictionary/nocebo|dictionary=Merriam-Webster|title=Merriam-Webster Online Dictionary}} {{L&S|noceo|ref}} in 1961 to denote the counterpart of placebo (Latin {{Wikt-lang|la|placēbō}}, "I shall please", from {{Wikt-lang|la|placeō}}, "I please"),{{OEtymD|placebo}} {{L&S|placeo|ref}} 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".{{sfn|Kennedy|1961}} That is, he rejected the use of the term for pharmacologically induced negative side effects such as the ringing in the ears caused by quinine.{{sfn|Kennedy|1961}} 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.{{sfn|Benedetti|Lanotte|Lopiano|Colloca|2007}}

In the narrowest sense, a nocebo response occurs when a drug-trial subject's symptoms are worsened by the administration of an inert, sham,{{sfn|Miller|2003}} or dummy (simulator) treatment, called a placebo. Placebos contain no chemicals (or any other agents) that could cause any of the observed worsening in the subject's symptoms, so any change for the worse must be due to some subjective factor. Adverse expectations can also cause anesthetic medications' analgesic effects to disappear.{{sfn|Bingel|Wanigasekera|Wiech|Ni Mhuircheartaigh|2011}}

The worsening of the subject's symptoms or reduction of beneficial effects is a direct consequence of their exposure to the placebo, but the placebo has not chemically generated those symptoms. Because this generation of symptoms entails a complex of "subject-internal" activities, we can never speak in the strictest sense in terms of simulator-centered "nocebo effects", but only in terms of subject-centered "nocebo responses". Some observers attribute nocebo responses (or placebo responses) to a subject's gullibility, but there is no evidence that someone 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.{{Cite journal|last1=Bishop|first1=Felicity L.|last2=Aizlewood|first2=Lizzi|last3=Adams|first3=Alison E. M.|date=2014-07-09|editor-last=Newman |editor-first=Christy Elizabeth|title=When and Why Placebo-Prescribing Is Acceptable and Unacceptable: A Focus Group Study of Patients' Views |journal=PLOS ONE|language=en|volume=9|issue=7 |pages=e101822|doi=10.1371/journal.pone.0101822|issn=1932-6203 |pmc=4089920|pmid=25006673 |bibcode=2014PLoSO...9j1822B |doi-access=free}}

Based on a biosemiotic model (2022), Goli explains how harm and/or healing expectations lead to a multimodal image and form transient allostatic or homeostatic interoceptive feelings, demonstrating how repetitive experiences of a potential body induce epigenetic changes and form new attractors, such as nocebos and placeboes, in the actual body.{{Citation |last=Goli |first=Farzad |title=Body, Meaning, and Time: Healing Response as a Transtemporal and Multimodal Meaning-Making Process |date=2022 |url=https://link.springer.com/10.1007/978-3-031-17678-4_6 |work=Epigenetics and Anticipation |series=Cognitive Systems Monographs |volume=45 |pages=79–97 |editor-last=Nadin |editor-first=Mihai |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/978-3-031-17678-4_6 |isbn=978-3-031-17677-7|url-access=subscription }}

It has been shown that, due to the nocebo effect, warning patients about drugs' side effects can contribute to the causation of such effects, whether the drug is real or not.{{sfn|Colloca|Miller|2011}}{{sfn|Barsky|Saintfort|Rogers|Borus|2002}} 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%.{{sfn|Stathis|Smpiliris|Konitsiotis|Mitsikostas|2013}} 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.{{sfn|Mitsikostas|Mantonakis|Chalarakis|2014}}

In January 2022, a systematic review and meta-analysis concluded that nocebo responses accounted for 72% of adverse effects after the first COVID-19 vaccine dose and 52% after the second dose.{{cite journal |last1=Haas |first1=Julia W. |last2=Bender |first2=Friederike L. |last3=Ballou |first3=Sarah |last4=Kelley |first4=John M. |last5=Wilhelm |first5=Marcel |last6=Miller |first6=Franklin G. |last7=Rief |first7=Winfried |last8=Kaptchuk |first8=Ted J. |title=Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine Trials: A Systematic Review and Meta-analysis |journal=JAMA Network Open |date=18 January 2022 |volume=5 |issue=1 |pages=e2143955 |doi=10.1001/jamanetworkopen.2021.43955 |pmid=35040967 |pmc=8767431 |issn=2574-3805}}{{cite news |last1=Smith |first1=Ian |title='Nocebo effect' cause of most COVID vaccine side effects, study says |url=https://www.euronews.com/next/2022/01/19/two-thirds-of-covid-vaccine-side-effects-caused-by-nocebo-effect-not-the-jab-itself-study- |work=euronews |date=19 January 2022 |language=en}}

Many studies show that the formation of nocebo responses are influenced by inappropriate health education, media work, and other discourse makers who induce health anxiety and negative expectations.{{Citation |last1=Goli |first1=Farzad |title=How to Prescribe Information: Health Education Without Health Anxiety and Nocebo Effects |date=2016 |url=http://link.springer.com/10.1007/978-3-319-35092-9_7 |work=Biosemiotic Medicine |volume=5 |pages=151–193 |editor-last=Goli |editor-first=Farzad |place=Cham |publisher=Springer International Publishing |doi=10.1007/978-3-319-35092-9_7 |isbn=978-3-319-35091-2 |last2=Monajemi |first2=Alireza |last3=Ahmadzadeh |first3=Gholam Hossein |last4=Malekian |first4=Azadeh|url-access=subscription }}

Researchers studying the side effects of statins in UK determined that a large proportion of reported side effects were related not to any pharmacological cause but to the nocebo effect. In the UK, publicity in 2013 about the apparent side effects caused hundreds of thousands of patients to stop taking statins, leading to an estimated 2,000 additional cardiovascular events in the subsequent years.

Evidence suggests that the symptoms of electromagnetic hypersensitivity are caused by the nocebo effect.{{sfn|Rubin|Nieto-Hernandez|Wessely|2009}}{{cite web | url=http://www.popsci.com/science/article/2010-02/disconnected | title=The Man Who Was Allergic to Radio Waves | work=Popular Science | date=4 March 2010 | access-date=1 December 2014 | author=Geary, James}}

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.{{cite journal |last1=Colloca |first1=Luana |title=The role of learning in nocebo and placebo effects. |journal=Pain |date= May 2008 |volume=136 |issue=1–2 |pages=211–218 |doi=10.1016/j.pain.2008.02.006 |pmid=18372113|s2cid=44220488 }} Nocebo hyperalgesia is believed to involve the activation of cholecystokinin receptors.{{sfn|Enck|Benedetti|Schedlowski|2008}}

Stewart-Williams and Podd argue that using the contrasting terms "placebo" and "nocebo" for inert agents that produce pleasant, health-improving, or desirable outcomes and unpleasant, health-diminishing, or undesirable outcomes (respectively) is extremely counterproductive.{{sfn|Stewart-Williams|Podd|2004}} For example, precisely the same inert agents can produce analgesia and hyperalgesia, the first of which, on this definition, would be a placebo, and the second a nocebo.{{sfn|Colloca|Benedetti|2007}}

A second problem is that the same effect, such as immunosuppression, may be desirable for a subject with an autoimmune disorder, but undesirable for most other subjects. Thus, in the first case, the effect would be a placebo, and in the second a nocebo.{{sfn|Stewart-Williams|Podd|2004}} A third problem is that the prescriber does not know whether the relevant subjects consider the effects they experience desirable or undesirable until some time after the drugs have been administered.{{sfn|Stewart-Williams|Podd|2004}} A fourth is that the same phenomena are generated in all the subjects, and 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 desirable to one group but not the other, the phenomena are now being labeled in two mutually exclusive ways (i.e., placebo and nocebo), giving the false impression that the drug in question has produced two different phenomena.{{sfn|Stewart-Williams|Podd|2004}}

Some people maintain that belief can kill (e.g., voodoo death: Cannon in 1942 describes a number of instances from a variety of different cultures) and or heal (e.g., faith healing).{{sfn|Cannon|1942}} A self-willed death (due to voodoo hex, evil eye, pointing the bone procedure,{{sfn|Zusne|Jones|1989|p=57}}{{sfn|Róheim|1925}} etc.) is an extreme form of a culture-specific syndrome or mass psychogenic illness that produces a particular form of psychosomatic or psychophysiological disorder resulting in psychogenic death. Rubel in 1964 spoke of "culture-bound" syndromes, 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".{{sfn|Rubel|1964}}

Certain anthropologists, such as Robert Hahn and Arthur Kleinman, have extended the placebo/nocebo distinction into this realm to allow a distinction to be made between rituals, such as faith healing, performed to heal, cure, or bring benefit (placebo rituals) and others, such as "pointing the bone", performed to kill, injure or bring harm (nocebo rituals). As the meaning of the two interrelated and opposing terms has extended, we now find anthropologists speaking, in various contexts, of nocebo or placebo (harmful or helpful) rituals:{{sfn|Hahn|Kleinman|1983}}

• 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;
• that 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 nocebo ritual's harmful nature or the placebo ritual's beneficial nature.

Yet it may become even more terminologically complex, for as Hahn and Kleinman indicate, there can also be cases of paradoxical nocebo outcomes from placebo rituals and placebo outcomes from nocebo rituals (see also unintended consequences).{{sfn|Hahn|Kleinman|1983}} In 1973, writing from his extensive experience of treating cancer (including more than 1,000 melanoma cases) at Sydney Hospital, Milton warned of the impact of the delivery of a prognosis, and how many of his patients, upon receiving their prognosis, gave up hope 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')".{{sfn|Milton|1973}}

Some researchers have pointed out that the harm caused by communicating with patients about potential treatment adverse events raises an ethical issue. To respect their autonomy, one must inform a patient about harms a treatment may cause. Yet the way in which potential harms are communicated could cause additional harm, which may violate the ethical principle of non-maleficence.{{Cite journal|last=Alfano|first=Mark|date=2015|title=Placebo effects and informed consent|journal=Am J Bioeth|volume=15|issue=10|pages=3–12|doi=10.1080/15265161.2015.1074302|issn=1745-6215|pmid=26479091|s2cid=45271769|url=https://philpapers.org/rec/ALFPEA}} It is possible that nocebo effects can be reduced while respecting autonomy using different models of informed consent, including the use of a framing effect{{cite journal |last1=Colloca |first1=Luana |last2=Finniss |first2=Damien |title=Nocebo effects, patient-clinician communication, and therapeutic outcomes. |journal=JAMA |date=8 February 2012 |volume=307 |issue=6 |pages=567–568 |doi=10.1001/jama.2012.11 |pmid=22318275|pmc=6909539 }} and the authorized concealment.

{{columns-list|colwidth=22em|

• Autosuggestion
• Clinical trial
• Placebo studies
• Psychosomatic illness
• Scientific control
• Self-fulfilling prophecy
• Subject-expectancy effect
• Suggestibility
• Suggestion
• Therapeutic effect
• Thomas theorem

}}

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• {{cite journal |doi=10.1006/pmed.1997.0229 |pmid=9327468 |title=Nocebo: The Power of Suggestibility |journal=Preventive Medicine |volume=26 |issue=5 |pages=616–621 |year=1997 |last1=Spiegel |first1=Herbert |s2cid=7017712 |doi-access=free }}
• {{cite journal |doi=10.1016/S0885-3924(97)00363-1 |pmid=9601159 |title=Suggestion/Placebo Effects on Pain |journal=Journal of Pain and Symptom Management |volume=15 |issue=4 |pages=235–243 |year=1998 |last1=Staats |first1=Peter |last2=Hekmat |first2=Hamid |last3=Staats |first3=Arthur |doi-access=free }}
• {{cite thesis | last=Stam | first=Henderikus |year=1982 | title=Hypnotic analgesia and the placebo effect: controlling ischemic pain |degree=PhD | publisher=Carleton University | doi=10.22215/etd/1982-00726 | doi-access=free}}
• {{cite journal |doi=10.1037/0021-843X.96.4.313 |title=Hypnotic analgesia, placebo analgesia, and ischemic pain: The effects of contextual variables |journal=Journal of Abnormal Psychology |volume=96 |issue=4 |pages=313–320 |year=1987 |last1=Stam |first1=Henderikus J. |last2=Spanos |first2=Nicholas P. |pmid=3693680 }}
• {{cite journal |doi=10.1111/ene.12014 |pmid=23145482 |title=Nocebo as a potential confounding factor in clinical trials for Parkinson's disease treatment: A meta-analysis |journal=European Journal of Neurology |volume=20 |issue=3 |pages=527–533 |year=2013 |last1=Stathis |first1=P. |last2=Smpiliris |first2=M. |last3=Konitsiotis |first3=S. |last4=Mitsikostas |first4=D. D. |s2cid=41163200 }}
• {{cite journal |doi=10.1037/0033-2909.130.2.324 |pmid=14979775 |title=The Placebo Effect: Dissolving the Expectancy Versus Conditioning Debate |journal=Psychological Bulletin |volume=130 |issue=2 |pages=324–340 |year=2004 |last1=Stewart-Williams |first1=Steve |last2=Podd |first2=John |s2cid=10297875 }}
• {{cite journal |doi=10.1126/scitranslmed.3001244 |pmid=21325618 |title=The Effect of Treatment Expectation on Drug Efficacy: Imaging the Analgesic Benefit of the Opioid Remifentanil |journal=Science Translational Medicine |volume=3 |issue=70 |pages=70ra14 |year=2011 |last1=Bingel |first1=U. |last2=Wanigasekera |first2=V. |last3=Wiech |first3=K. |last4=Ni Mhuircheartaigh |first4=R. |last5=Lee |first5=M. C. |last6=Ploner |first6=M. |last7=Tracey |first7=I.|author7-link=Irene Tracey|s2cid=207775719 }}
• {{cite book |last1=Wilson |first1=Ian |title=The Bleeding Mind: An Investigation into the Mysterious Phenomenon of Stigmata |publisher=Paladin |location=London |year=1991 |isbn=978-0-586-09014-5 }}
• {{cite book |last1=Zusne |first1=L. |last2=Jones |first2=W.H. |title=Anomalistic Psychology: A Study of Magical Thinking |edition=2nd |publisher=Lawrence Erlbaum Associates |location=New York |year=1989 }}

{{div col end}}

{{Wiktionary}}

{{Commons category|Nocebos}}

• [http://skepdic.com/nocebo.html Nocebo and nocebo effect]
• [https://web.archive.org/web/20060822062832/http://www.hmiworld.org/hmi/issues/May_June_2005/around_nocebo.html The nocebo response]
• [https://web.archive.org/web/20080907091040/http://www.washingtonpost.com/ac2/wp-dyn/A2709-2002Apr29 The Nocebo Effect: Placebo's Evil Twin]
• [https://web.archive.org/web/20061118085906/http://www.studentbmj.com/issues/02/02/education/12.php What modifies a healing response]
• [https://www.newscientist.com/article/mg20227081.100-the-science-of-voodoo-when-mind-attacks-body.html?full=true&print=true The science of voodoo: When mind attacks body, New Scientist]
• [https://www.science.org/doi/abs/10.1126/scitranslmed.3001244 The Effect of Treatment Expectation on Drug Efficacy: Imaging the Analgesic Benefit of the Opioid Remifentanil]
• [https://www.youtube.com/watch?v=O2hO4_UEe-4&list=PLqs5ohhass_QZtSkX06DmWOaEaadwmw_D&index=3 This Video Will Hurt (The Nocebo Effect)], via YouTube
• [http://www.bbc.co.uk/programmes/p02kmqvb BBC Discovery program on the nocebo effect]
• [http://www.smithsonianmag.com/science-nature/what-is-the-nocebo-effect-5451823/?no-ist What is the Nocebo effect?]

{{unintended consequences}}

{{Authority control}}

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