The Nocebo Effect Edward Wei

'THE NOCEBO EFFECT' Selyn Lim (Year 11, Wu)

Edward Wei (Year 10, Peel)

The nocebo effect is a hypothesis that proposes the negative expectations of procedures or situations can lead to, or worsen, symptoms. It is a recondite feature of society that could be responsible for a variety of diseases around the world [1]. The term nocebo, Latin for “I will harm”, was coined by Walter Kennedy in 1961 [2]. You may be more familiar with its counterpart - the placebo effect (Latin for “I will please”), beneficial effects brought upon by expectations of positive outcomes when taking drugs or undergoing treatments. Both nocebo and placebo are considered nonspecific effects of medical treatments, meaning that they are the results of an intervention that do not result from a specific diagnosis or explanation. It is called the placebo effect when positive and nocebo effect when negative [3]. Both nocebo and placebo effects are seen as psychobiological phenomena arising from a therapeutic context [4].

Figure 1: Picture depicting the nocebo effect (Source: https://braininlabor.com/2018/01/23/nocebo-effect/)

THE MECHANISM BEHIND NOCEBO

Several factors may cause a nocebo effect in patients by prompting negative expectations of the situation in various ways. The negative expectancies can be induced verbally like being told of the side effects by the behaviour of the provider or by the patient-physician relationship. For example, in one study (Howe et al. 2017), patients were induced with allergic reactions through a histamine skin test and then given a cream with no active ingredients by a healthcare provider who demonstrated either high or low warmth, and high or low competence. They were then told that the cream would either increase or reduce the allergic reaction. The result was that those who the caretaker treated with high warmth and high competence experienced better results according to the expectations they have of the effects of the cream and vice versa [6]. In addition, the use of certain words can increase or decrease the extent of nocebo. For example, prior to the injection of a local anaesthetic, “pain” resulted in more pain as opposed to “a cool sensation”. This is the same for “you will feel a bee sting” resulting in more pain than “it will numb the area ” (Wells 2012) [7].

The characteristics of the patient can also determine the chances of the nocebo effect taking place. Those with aggressive and competitive personalities tend to experience nocebo more, being 94% more likely to report side effects (Drici et al. 1995) in an experiment where 52 participants (26 males and 26 females) were separated into the competitive and aggressive group and non-competitive and passive group according to the Bortner Rating Scale. Each subject then received a drop of placebo in one eye and a drop of the

active drug in another 4 times a day for a week. However, it is also possible that the higher vulnerability of competitive and aggressive people could be attributed to their generally more stressful lives rather than a direct result of their personality [8]. Women also seem to be more susceptible to nocebo than men, as seen in an experiment where 48 healthy men and women received a salient oral stimulus and a verbal suggestion that it would enhance nausea. They were rotated once as a control group then separated into 2 equal groups of women and men. One group was given the stimulus then rotated once per day for 3 days to examine how they would respond to conditioning. Another group was given the stimulus then rotated 5 times each for 1 minute to test how they would respond to expectancy. The experiment concluded that women responded stronger to conditioning-induced nocebo and men responded to expectancy-induced nocebo but to a lesser extent [9]. It was also noted that optimists responded to placebo more while pessimists responded to nocebo more [10].

Furthermore, nocebo effects have some emotional and neurobiological correlations (Schienle et al. 2018). It involved 38 women being shown images of disgusting, fear-inducing and neutral categories while presented with an odourless stimulus of distilled water with green food colouring together with the verbal suggestion that the fluid smells bad. 76% of women (29) perceived a slightly unpleasant odour and the disgusting smell experienced increased when viewing disgusting images, while the last 9 reported no response [11].

Past experiences of the patient can also contribute to nocebo [12]. As shown in one study (Witthoft 2012), participants were randomly assigned to watch a television report about the adverse effects of WiFi and then exposed to a fake WiFi signal. 54% of the 147 participants reported symptoms which they attributed to the fake exposure. Moreover, participants who have been exposed to similar reports on adverse effects of WiFi were 22% more likely to experience nocebo in the experiment [13].

ETHICAL IMPLICATIONS OF NOCEBO

Figure 2: The extent of nocebo effect in increasing risks of adverse effects (Source: ResearchGate)

Due to the nature of nocebo, it has raised many ethical issues because testing nocebo can be quite painful, and even potentially dangerous for subjects. In one experiment, a 26-year-old male took 29 inert capsules believing he was overdosing on an antidepressant. He subsequently experienced hypertension requiring intravenous fluids to maintain adequate blood pressure until the true nature of the capsules was revealed, after which the effects dissipated within 15 minutes [14]. Furthermore, nocebo leads to quite a dilemma. On one hand, physicians are obligated by law to inform the patient of any adverse effects. On the other hand, it is the physician’s duty to minimize any risks of treatment suggesting that informing patients should not be done as it could lead to nocebo increasing the risk of harmful effects. There are several strategies to reduce this dilemma. One is using more positive language to describe adverse effects. Two is by permitting non-information, allowing the patient to decide whether or not to know the detrimental effects while cautioning them that knowing the effects could increase the risks of potential issues. Finally, properly educating the patient has also been shown to reduce the effects of nocebo [4, 15]. These are not

perfect solutions though; effectiveness varies across different cultures and different personalities. Some people may subconsciously view the act of trying to withhold information as hiding how dangerous the treatment may be [16].

THE NEUROBIOLOGY OF NOCEBO

For quite some time, neurologists believed that the presence of nocebo responses is evidence of symptom exaggeration or evidence that symptoms are psychogenic rather than organic. However, this has been disputed as many animal trials (and less commonly, human trials) have shown that nocebo can induce actual physiological changes [17]. Such experiments include exposing guinea pigs or humans to things they are allergic to, like chocolate, while exposing them to a stimulus, such as an auditory cue, once or several times a day. Thus they become conditioned to have an allergic response every time they are exposed to the conditioned stimulus, even when the actual substance they are allergic to is not present [18]. Another piece of evidence that supports the neurobiological mechanisms of nocebo is that certain antagonist drugs (chemicals that inhibit a physiological action) and agonist drugs (chemicals that encourage or start a physiological action) can stop nocebo responses, such as in an experiment that found that proglumide - an antagonist chemical - could prevent nocebo-induced hyperalgesia (a condition where patients develop an increased sensitivity to pain) [17].

The effects of nocebo seem to be related to anxiety as shown in the workings of Fabrizio Benedetti, a professor of physiology and neuroscience at the University of Turin Medical School in Italy. The expectancy of something bad happening induces anxiety and causes the secretion of neurotransmitter cholecystokinin, or CCK (CCK also functions as a hormone that stimulates the digestion of protein and fat). CCK facilitates negative feelings like pain, so when CCK antagonists were given, it stopped nocebo generated pain (the aforementioned proglumide is a CCK antagonist). However, CCK antagonists don’t work against placebo, proving that while the effects of placebo and nocebo are similar, the mechanisms behind them are slightly different [19].

CONCLUSION

Figure 3: Venn diagram of all different factors that could play a role in placebo and nocebo effects. (Source: PubMed)

Nocebo is the lesser-known “evil twin” of placebo. It is caused by many different factors that can be divided into 3 components: expectations, beliefs and past experiences of the patient, the expectations and beliefs of the physician and beliefs and expectations engendered within the relationship between the

two parties. Its effects are surprisingly powerful - so long as one’s belief is powerful enough, it can even cause death. Understanding how nocebo works is critical in medicine to reduce the risks of the adverse effects of various treatments and improving the evaluation of the true effects of new drugs.

BIBLIOGRAPHY

1. https://www.sciencedirect.com/science/article/pii/S0091743596901243?via%3Dihub 2. https://psychcentral.com/blog/the-other-side-of-the-placebo-effect/ 3. https://ptpodcast.com/understanding-specific-and-non-specific-effects/ 4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401955/ 5. https://www.sciencedirect.com/sdfe/pdf/download/eid/1-s2.0-S0091743597902280/first-pagepdf 6. https://psycnet.apa.org/buy/2017-10534-001 7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352765/ 8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364964/ 9. https://www.sciencedirect.com/science/article/abs/pii/S0022399908004716 10. https://www.youtube.com/watch?v=opc3tYHbKV4 11. https://link.springer.com/article/10.1007/s11682-017-9675-1 12. https://www.sciencedirect.com/sdfe/pdf/download/eid/1-s2.0-S0091743597902280/first-pagepdf 13. https://www.sciencedirect.com/science/article/abs/pii/S0022399912003352 14. https://www.sciencedirect.com/science/article/abs/pii/S0163834307000114?via%3Dihub 15. https://www.researchgate.net/publication/302780910_Nocebo_Effects_The_Dilemma_of_

Disclosing_Adverse_Events 16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655643/ 17. https://neuro.psychiatryonline.org/doi/full/10.1176/appi.neuropsych.13090207 18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130401/ 19. https://www.vice.com/en_us/article/59xe9b/the-power-of-the-nocebo-effect-v26n1

GENERAL https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804316/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176716/ https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00555/full#B30