'Nocebo' effect may cause two-thirds of COVID-19 vaccine reactions, study suggests

Two-thirds of adverse reactions reported with the COVID-19 vaccine, such as headaches and fatigue, could be due to a negative version of the placebo effect, according to a US study published in JAMA Network Open.

A woman wearing a white vest as a blue-gloved hand of a healthcare professional are seen injecting a vaccine.
The 'nocebo' effect occurs when a person experiences unpleasant side-effects after taking a treatment with no pharmacological effects. | GETTYIMAGES

In a meta-analysis of 12 randomised, placebo-controlled COVID-19 vaccine trials, researchers at Beth Israel Deaconess Medical Center compared the rates of adverse reactions reported by participants who received the vaccines (n=22,802) to the rates of adverse reactions reported by those who received a placebo injection containing no vaccine (n=22,578).

After the first dose 35.2% (95% CI, 0.267–0.437) of placebo recipients experienced systemic adverse reactions with headache and fatigue most common; 16.2% (95% CI, 0.113–0.211) reported at least one local reactions, including redness, swelling or pain at the site of injection. In contrast, 46.3% (95% CI, 0.382–0.543) of vaccine recipients experienced at least one systemic adverse reaction and 66.7% (95% CI, 0.532–0.803) reported at least one local reaction. 

After the second dose, adverse reactions among the placebo group dropped to 31.8% (95% CI, 0.287–0.35) reporting any systemic reactions and 11.8% (95% CI, 0.066–0.171) reporting any local reactions. In comparison, vaccine recipients reported more reactions, with 61.4% (95% CI, 0.474–0.754) reporting systemic reactions and 72.8% (95% CI, 0.574-0.882) reporting local reactions.

Nocebo effect

Although vaccine recipients were more likely to experience both systemic and local adverse reactions than placebo recipients, researchers found that 76% of systemic reactions and 24.3% of local reactions following the first dose and 51.8% of systemic reactions and 16.2% of local reactions following the second dose could be attributed to the 'nocebo' effect. 

The rates of adverse reactions in the placebo groups were lower after the second dose than after the first, however the opposite was true for the vaccine groups. Researchers said 'while the reason for this relative decline in nocebo effects cannot be confirmed, the researchers believe that the higher rate of adverse events in the vaccine group the first time may have led participants to anticipate more the second time.'

Inform the public

'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,' said Ted Kaptchuk, senior author, director of the Program in Placebo Studies and the Therapeutic Encounter at BIDMC and professor of medicine at Harvard Medical School. '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. 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.' he concluded. 

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