Around one in three people who got a placebo injection as part of a COVID-19 vaccine trial reported systemic side effects like headache and fatigue.
The placebo effect is a well-known occurrence in which a person’s physical or mental health improves after receiving a therapy that has no pharmacological therapeutic benefit — for example, a sugar pill or a syringe full of saline.
While the specific pharmacological, psychological, and genetic roots of the placebo effect are unknown, some theories attribute it to expectations, while others suggest that non-conscious variables ingrained in the patient-physician connection automatically reduce the volume of symptoms.
Placebo effects can sometimes be harmful; for example, the so-called “nocebo effect” occurs when a person experiences unpleasant side effects after taking a treatment that has no pharmacological effects.
It’s the same sugar pill making you sick, or the saline injection making you tired.
Researchers at Beth Israel Deaconess Medical Center (BIDMC) conducted a meta-analysis of randomized, placebo-controlled COVID-19 vaccine trials, comparing the prevalence of adverse events reported by vaccine recipients to those who got a placebo injection containing no vaccine.
While the investigators discovered that study participants who received the vaccine reported much more adverse events, roughly a third of those who received the placebo also confirmed at least one unexpected reaction, the most prevalent of which were headache and fatigue.
“Adverse events after placebo treatment are common in randomized controlled trials,” says lead author Julia W. Haas. “Collecting systematic evidence regarding these nocebo responses in vaccine trials is important for COVID-19 vaccination worldwide, especially because concern about side effects is reported to be a reason for vaccine hesitancy.”
Haas and colleagues looked at data from 12 COVID-19 vaccination clinical trials. A total of 22,578 placebo patients and 22,802 vaccination recipients were involved in the 12 studies.
Following the initial injection, more than 35% of placebo recipients reported systemic adverse events – symptoms involving the entire body, such as fever – with headache and fatigue being the most prevalent, occurring in 19.6% and 16.7% of recipients, respectively.
More than a third or 16% of placebo patients reported at least one local incident, such as discomfort, redness, or swelling at the injection site.
In comparison, 46% of vaccine recipients reported experiencing at least one systemic adverse event following the initial injection, while two-thirds reported experiencing at least one local adverse event. While this group got a pharmacologically active treatment, at least part of their adverse events can be attributed to the placebo – or in this case, nocebo – effect, as many of these outcomes happened in the placebo group as well. In their study, Haas and his colleagues found that nocebo was responsible for 76% of all vaccine-related side effects and almost a quarter of all local effects.
After the second shot, the placebo group’s adverse events decreased to 32% reporting any systemic events and 12% reporting any local effects. Participants who received the vaccine, on the other hand, reported higher side effects, with 61% reporting systemic and 73% reporting local adverse events.
Nocebo was shown to be responsible for approximately 52% of the negative effects observed after the second dose, according to the study.
While the explanation for this relative drop in nocebo effects is unknown, the researchers suspect that the vaccine group’s higher rate of adverse outcomes the first time may have increased participants’ anticipatory behavior the second time.
“Nonspecific symptoms like headache and fatigue – which we have shown to be particularly nocebo sensitive – are listed among the most common adverse reactions following COVID-19 vaccination in many information leaflets,” adds senior author Ted J. Kaptchuk.
“Evidence suggests that this sort of information may cause people to misattribute common daily background sensations as arising from the vaccine or cause anxiety and worry that make people hyper alert to bodily feelings about adverse events.”
“Medicine is based on trust,” adds Kaptchuk. “Our findings lead us to suggest that informing the public about the potential for nocebo responses could help reduce worries about COVID-19 vaccination, which might decrease vaccination hesitancy.”
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