The curious case of ‘A’ and the psychology at play in medical trials.
Most of us know about the placebo effect, but how many of us are aware of the “nocebo” effect?
This strange yet powerful phenomenon can influence everything from health outcomes to the symptoms we experience following medical treatment. It is also surprisingly common. So, what exactly is the nocebo effect, and how can we avoid it?
A study in strange
In 2007 a case study was published in General Hospital Psychiatry that highlighted the powerful phenomenon known as “the nocebo effect.”
The case study detailed the experience of A — a 26-year-old-man enrolled in a clinical drug trial investigating the effectiveness of an antidepressant medication. A had been depressed for two months before commencing the trial, following the end of a romantic relationship.
After completing the first month of the trial, A reported a significant improvement in his mood. He had just begun his second month of treatment when he had an argument with his girlfriend – leading to the decision to take all remaining 29 capsules.
A presented to the hospital asking for help before collapsing. On assessment, he was noted to be pale and sweating heavily. His blood pressure was abnormally low, and his pulse elevated. Despite receiving six litres of intravenous fluids over four hours, A remained sluggish and his blood pressure and heart rate remained abnormal. At this point, a doctor from the drug trial arrived at the hospital, advising that the capsules Mr A had taken were not a medication but a placebo (inactive substance). Within 15 minutes of receiving this news, A was alert and his blood pressure and pulse had returned to within normal limits.
The nocebo effect
The “nocebo effect” is the name given to the phenomenon whereby an individual experiences negative side effects due to the belief that a substance or intervention is harmful. In essence, the nocebo effect is the opposite of the placebo effect.
“I think the best way to describe the nocebo effect is to tell the story of A,” says Dr Kate Faasse, a senior lecturer in health psychology at the University of New South Wales in Sydney. “It’s a dramatic example, but a helpful one to illustrate what it might look like and the power of nocebo effects.”
The nocebo effect is not caused by the active ingredients of a procedure, but rather by psychological contextual factors such as expectations, past experiences, empathy, the interaction itself, and all sorts of factors that we are discovering . . . some symptoms are also just common everyday symptoms that people experience anyway and then mistakenly attribute as a treatment side effect.
Faasse has been studying the nocebo effect for more than a decade – inducing physical symptoms in unsuspecting participants by informing them about potential ‘side effects.’
“I study the nocebo effect as side effects,” says Faasse, “so, medication side effects that aren’t caused by anything in the medication itself. In our studies, we give people placebos, so we know for sure that anything they’re experiencing is not caused by the medication itself.”
In her research, Faasse uses cover stories and props to ensure participants are none-the-wiser regarding the purpose of her studies.
“For example we’ll say, ‘this is a nasal oxytocin spray, and we’re testing what it does with trust and cooperation.”
“It’s really saline but we warn participants about a list of side effects. And I think in every study I have done in my career — bar one — we’ve generated nocebo effects.”
‘More common than not’
Nocebo effects are surprisingly common. A meta-analysis published in the European Journal of Neurology found that 67.2 percent of placebo-treated patients in clinical trials involving fibromyalgia medications, reported at least one adverse effect. Similarly, a separate meta-analysis published in the Journal of Crohn’s and Colitis, found 70.6 percent of placebo-treated patients in clinical trials involving treatments for Crohn’s disease, to have reported adverse effects.
“It’s more common than not, basically,” says Faasse.
“I think, under the right circumstances, all of us have the capacity to experience nocebo effects. And I suspect pretty much all of us have – particularly given that they’re actually more common than treatment side effects.”
Research has identified several factors that increase the likelihood of experiencing nocebo effects. These include the suggestion side effects may be experienced due to a medication or procedure, individual perceptions that a medication dose is higher than usual, an increased expectation of experiencing side effects, and conditioning – whereby previous experience with treatment leads to learned associations.
Another significant predictive factor for the nocebo effect is social modelling – seeing another person experience or report side effects.
“Social modelling is a really good way to increase the nocebo effect,” says Faasse. “It quite meaningfully increases nocebo effects – particularly in women.”
The cost of expectation
The nocebo effect is an important aspect of patient care because it has the power to influence treatment outcomes, and while many are unaware that the nocebo effect even exists, this does not mean protection from its reach. “Most people don’t realise that there are psychological influences on side effects,” says Faasse.
“I think the biggest misunderstanding is the assumption or belief that anything that happens after you take a pill or new treatment is caused by that pill or treatment, which from my perspective is highly unlikely to be the case.”
But Faasse emphasises that the experience of nocebo effects does not mean that side effects are ‘in your head’.
“These things are really happening,” says Faasse, “our brains are incredibly good at creating these symptomatic experiences and making us feel unwell.”
The nocebo effect also carries with it potentially negative health-related outcomes. The experience of nocebo effects, for example, may result in the discontinuation of necessary medical treatment. And for patients who continue with treatment despite nocebo effects, these side effects may cause significant discomfort. “It doesn’t matter whether it’s a nocebo effect or if it’s an actual treatment effect,” says Faasse, “it’s still unpleasant and distressing.”
A potential increase in the cost of treatment is another consideration when it comes to the nocebo effect.
Indeed, research has shown patients often assume generic medications carry more side effects than brand-name equivalents. And as generic labelling — opposed to brand-name labelling — is associated with increased nocebo effects, patients may choose to pay for more costly brand-name medications when generic versions are identical.
Reducing nocebo effects
When it comes to the nocebo effect, consent is a double-edged sword.
While physicians are legally obliged to inform patients about the potential side effects of treatment, this can also increase the likelihood that side effects will be experienced. So, how do we reduce nocebo effects?
“We need to tell people about possible side effects,” says Faasse, “but we can do that in a different way … framing side effect information with a focus on the positive can significantly reduce the nocebo effect.”
Indeed, a review by Faasse and colleagues found that of the relatively few empirical studies that have examined the effect of positive framing on nocebo effects, five out of six demonstrated a significant reduction in at least one aspect of side effects when positive framing was used.
Offering choice regarding medical treatment is another possible way to reduce the nocebo effect. “When we offer people a limited choice we can actually knock out the nocebo effect or substantially reduce it.”
In a study published in Annals of Behavioral Medicine, Faasse and colleagues found that placebo treated participants who were offered a choice between two ‘medical treatments’, reported significantly less side-effects than when compared to those participants who were assigned treatment without choice. So, if two choices are good, then more must be better? Unfortunately, no.
“When we gave people a choice of 10 different medications,” says Faasse, “we brought those nocebo effects right back. So, we need to find the sweet spot in terms of giving people some control in their healthcare . . . but those are future studies.”
Originally published by Cosmos as The nocebo effect: How your brain might be working against you
Deborah Johanson is a freelance medical and science writer from Auckland, New Zealand. She holds a PhD and Masters degree in Health Psychology, a Bachelors degree in Health Science, and has a clinical background as a Registered Nurse. While most of her research has involved healthcare robots, Deborah now writes about health, medicine, technology, and science.