The Nocebo Effect

Most of us have heard of the placebo effect – the phenomenon in which patients experience improvements in health simply due to their belief in the efficacy of a medical treatment that lacks any real therapeutic function (named for the Latin placere, meaning “I will please”). But what of the reverse? For some patients, the mere belief that a substance may have detrimental side effects creates a negative health outcome. This phenomenon is known as the nocebo effect, named for the Latin nocere, or “I will harm.” This opposite tendency is one that has been largely overlooked and remains poorly understood. However, the nocebo effect can have a significant impact on clinical practice and drug development.

The nocebo response, defined as new, negative symptoms that are caused without any active treatment, may come into play through two mechanisms: classical pavlovian conditioning, and suggestion (Enck et al., 2008). As an example of conditioning, in one study (Klosterhalfen et al., 2009), subjects were seated in a rotation chair to invoke nausea, and symptom ratings associated with motion sickness were collected. Subjects being conditioned were given cinnamon gum immediately before these rotation sessions, while control subjects were given the gum at an unrelated time. Those who were in the conditioned group learned to associate the taste of the gum with the feelings of nausea, and on the last day of the experiment reported feeling motion sickness symptoms after chewing the gum – before even getting into the rotation chair. As for the power of suggestion, another study divided patients with chronic back pain into two groups. One group was told that a leg flexion test might lead to a slight increase in pain, while the other was told that the test would have no effect on pain level. The group to which the possibility of pain had been suggested reported significantly stronger pain intensity than the other group (Pfingsten et al., 2001).

Instances of the nocebo phenomenon have also been reported in clinical trials for drug development. In one such trial, two of the three study centers informed participants about possible gastrointestinal side effects, leading to a six-fold rise in the rate of participant dropout due to self-reported gastrointestinal issues, even though the three study centers showed no differences in the frequency of physical gastrointestinal issues (i.e. gastrointestinal bleeding, gastric or duodenal ulcers) (Myers et al., 1987). In another, a whopping 44% of patients who had been informed of possible erectile dysfunction (ED) as a side effect of a drug to treat prostate disease reported having ED, compared to only 15% of patients who were not briefed on this possible side effect (Mondaini et al., 2007). The verbal and non-verbal communications between physicians or nursing staff and patients may also trigger a nocebo response. For example, in one study, injection of a local anesthetic was announced to patients by saying either “We are going to give you a local anesthetic that will numb the area so that you will be comfortable during the procedure” or “You are going to feel a big bee sting; this is the worst part of the procedure.” Unsurprisingly, patients’ perceived pain was significantly greater after hearing the latter sentence (Varelmann et al., 2010).

The nocebo effect presents an important ethical dilemma in treatment development and medical practice. On the one hand, physicians and researchers have the obligation to tell patients and study participants about possible negative effects for purposes of informed consent. On the other hand, multiple studies show that communicating this foreboding information can cause harm to the participant (Miller & Colloca, 2011). To address this issue, it is suggested for physicians and researchers to re-frame their language to focus on the positive. A study on briefing in the context of flu vaccination told one group the proportion of individuals that tolerated the vaccine well, while the other group was told the proportion that experienced negative effects. Fewer adverse events were reported after the vaccine by the group that was informed of the “well-tolerated” statistic (O’Connor et al., 1996). Another recommendation is to ask participants to consent to remaining uninformed about certain negative mild side effects (although it is of course still necessary to inform them about severe and/or irreversible effects). Patients could even be given a list of categories of possible adverse events for any given medication or procedure, thus allowing each patient to decide which categories of side effects they would want to be briefed about (Häuser et al., 2012). The nocebo effect can certainly cause tension between the obligation of informed consent and the obligation to do no harm, but perhaps its cure is simple: improved communication training, so that researchers and physicians can harness the power of words for the benefit, rather than the detriment, of their participants and patients.

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Written by Elizabeth Burnette

Edited by Sean Noah, Desislava Nesheva and Arielle Hogan

Illustrated by Gil Torten

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References

Enck, P., Benedetti, F., & Schedlowski, M. (2008). New insights into the placebo and nocebo responses. Neuron, 59(2), 195–206. https://doi.org/10.1016/j.neuron.2008.06.030

Häuser, W., Hansen, E., & Enck, P. (2012). Nocebo phenomena in medicine: Their relevance in everyday clinical practice. Deutsches Arzteblatt International, 109(26), 459–465. https://doi.org/10.3238/arztebl.2012.0459

Klosterhalfen, S., Kellermann, S., Braun, S., Kowalski, A., Schrauth, M., Zipfel, S., & Enck, P. (2009). Gender and the nocebo response following conditioning and expectancy. Journal of Psychosomatic Research, 66(4), 323–328. https://doi.org/10.1016/j.jpsychores.2008.09.019

Miller, F. G., & Colloca, L. (2011). The placebo phenomenon and medical ethics: Rethinking the relationship between informed consent and risk-benefit assessment. Theoretical Medicine and Bioethics, 32(4), 229–243. https://doi.org/10.1007/s11017-011-9179-8

Mondaini, N., Gontero, P., Giubilei, G., Lombardi, G., Cai, T., Gavazzi, A., & Bartoletti, R. (2007). Finasteride 5 mg and sexual side effects: How many of these are related to a nocebo phenomenon? The Journal of Sexual Medicine, 4(6), 1708–1712. https://doi.org/10.1111/j.1743-6109.2007.00563.x

Myers, M. G., Cairns, J. A., & Singer, J. (1987). The consent form as a possible cause of side effects. Clinical Pharmacology and Therapeutics, 42(3), 250–253. https://doi.org/10.1038/clpt.1987.142

O’Connor, A. M., Pennie, R. A., & Dales, R. E. (1996). Framing effects on expectations, decisions, and side effects experienced: The case of influenza immunization. Journal of Clinical Epidemiology, 49(11), 1271–1276. https://doi.org/10.1016/s0895-4356(96)00177-1

Pfingsten, M., Leibing, E., Harter, W., Kröner-Herwig, B., Hempel, D., Kronshage, U., & Hildebrandt, J. (2001). Fear-avoidance behavior and anticipation of pain in patients with chronic low back pain: A randomized controlled study. Pain Medicine (Malden, Mass.), 2(4), 259–266. https://doi.org/10.1046/j.1526-4637.2001.01044.x

Varelmann, D., Pancaro, C., Cappiello, E. C., & Camann, W. R. (2010). Nocebo-induced hyperalgesia during local anesthetic injection. Anesthesia and Analgesia, 110(3), 868–870. https://doi.org/10.1213/ANE.0b013e3181cc5727