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Sticks and stones may break my bones, but words can never hurt me. But what if words could hurt you? Meet the nocebo effect, the evil twin of placebo. The nocebo effect is an increase in negative symptoms in response to patient expectations. This occurs in both clinical trials and normal clinical care. In clinical trials, this frequently presents as adverse events occurring during a placebo administration (such as a sugar pill instead of a blood pressure med), but it’s important to note that nothing needs to be administered for an increase in symptoms. Nocebo effects may sound like no big deal, but symptoms can be significant. In clinical trials, 4-26% of patients who discontinue medication do so because of nocebo reactions.  Unfortunately this burden isn’t evenly spread. Women experience an outsized effect, as do those suffering from certain psychiatric illnesses, such as anxiety and depression. Furthermore, both pessimistic and type A individuals experience higher rates of nocebo effect.

So how does it work, and are the effects real? Nocebo effects are due to our own expectations. When a doctor, nurse, or researcher states the potential side effects for a medication or procedure, patients are more likely to experience those effects. This has been shown in several anecdotal settings, but also in multiple research studies. During the COVID clinical trials, patients were reporting serious side effects that tracked popular media descriptions – even when they were given saline instead of the real vaccine!

These effects show the power of negative expectations, one of the three psychological mechanisms underpinning the nocebo effect. Negative results are a direct result of expectations. Researchers in one study tested the effect of word phrasing on pain outcomes. When pregnant women were preparing to get an anesthesia injection the researchers talked them through what might happen. Half the patients were given the standard spiel, “You are going to feel a big sting and burn in your back now”. The other half were given the same information in much more neutral language: “We are going to inject the local anesthetic that will numb the area.“ The neutral language group experienced significantly less pain during the injection – just from phrasing! Scientists think the negative expectations might increase focus on symptoms. The expectations don’t have to come just from doctors or nurses, however. Seeing someone else suffer a side effect or hearing stories can produce the same effect!

Two other psychological underpinnings for the nocebo effect are less direct. Misattribution is the blaming of normal aches and pains to a new medicine. Progressive disease effects can also be misattributed to a placebo medication. Finally, conditioning has a large effect. Conditioning is the long-term associations we make between seemingly related things. Some patients feel nauseous at the smell of a hospital, for instance. This can also be very specific; the color of a pill can induce distinct side effects. Patients taking blue sugar pills are more likely to experience and report drowsiness than those taking pink sugar pills. Psychology shows us the framework for understanding what’s happening, but what’s going on under the hoodie?

Our brains experience changes at suggestions. Scientists think these changes may be due in large part to anticipatory anxiety. Anticipatory anxiety activates at least two pathways in the brain: pain and stress. Part of the pain pathway is called the CCKergic pronociceptive [pro-no-si-cep-tive] system. It is activated by a peptide called cholecystokinin [kow·luh·si·stuh·kai·nuhn] (CCK), and increases our perception of pain at the spinal level. This undermines anesthesia and increases our feelings of pain. The stress pathway moves through a few brain regions along the hypothalamus–pituitary–adrenal (HPA) axis and produces cortisol. Cortisol is a hormone that causes all of the classic signs of stress – increased heart rate and blood pressure, sweating and breathing, among others. The activation of these two major pathways primes our brain and bodies to experience worse symptoms – especially those we are expecting.

So what can be done? Well, reading this article is a great start! Around 75% of patients haven’t heard of or don’t believe in the nocebo effect, even though they experience it. Thinking about risks in terms of percentages instead of raw numbers can help. Four in a thousand may increase anxiety more than 0.4%.Other methods may be in the hands of medical professionals. Positive framing, such as with the injection example above, can make a lot of difference. In addition, identifying risky patients may help with how information is presented. Fortunately, understanding the mechanistic nature behind the nocebo effect can help lessen your anxiety – and symptoms!

Written By Benton Lowey-Ball, BS Behavioral Neuroscience

Sources:

Kong, J., Gollub, R. L., Polich, G., Kirsch, I., LaViolette, P., Vangel, M., … & Kaptchuk, T. J. (2008). A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect. Journal of Neuroscience, 28(49), 13354-13362. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649754/

Planès, S., Villier, C., & Mallaret, M. (2016). The nocebo effect of drugs. Pharmacology research & perspectives, 4(2), e00208. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804316/

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