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More than two-thirds of adverse COVID-19 vaccine events are due to placebo effect

Vaccine Fight Virus

One-third of clinical trial participants who did not receive any vaccine reported systemic side effects such as headache and fatigue.

The placebo effect is the well-known phenomenon in which a person's physical or mental health improves after taking a treatment without pharmacological therapeutic benefit - for example, a sugar pill or a syringe full of saline. While the exact biological, psychological, and genetic underpinnings of the placebo effect are not well understood, some theories point to expectations as the primary cause, and others argue that non-conscious factors embedded in the patient-physician relationship automatically reduce the amount of symptoms. Sometimes placebo effects can also be harmful - the so-called "nocebo effect" occurs when a person experiences unpleasant side effects after taking a treatment without pharmacological effect. The same sugar pill that causes nausea, or the syringe full of saline that results in fatigue.

In a new meta-analysis of randomized, placebo-controlled COVID-19 Vaccine trials compared researchers at Beth Israel Deaconess Medical Center (BIDMC) the frequency of adverse reactions reported by participants who received the vaccines with the rate of adverse reactions reported by those who received a placebo injection without a vaccine. While the researchers found significantly more trial participants who received the vaccine reported side effects, nearly one-third of the participants who received placebo also reported at least one side effect, with headaches and fatigue being the most common. The team's results are published in JAMA Network Open.

"Adverse events following placebo treatment are common in randomized controlled trials," said lead author Julia W. Haas, PhD, an investigator in the BIDMC placebo studies program. "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 cause of vaccination dust."

Haas and colleagues analyzed data from 12 clinical trials with COVID-19 vaccines. The 12 trials included adverse reaction reports from 22,578 placebo recipients and 22,802 vaccine recipients. After the first injection, more than 35 percent of placebo recipients experienced systemic side effects - symptoms affecting the whole body, such as fever - with headaches and fatigue most common at 19.6 percent and 16.7 percent, respectively. Sixteen percent of placebo recipients reported at least one local event, such as injection site pain, redness, or swelling.

By comparison, after the first injection, 46 percent of vaccine recipients experienced at least one systemic side effect, and two-thirds of them reported at least one local event. While this group received a pharmacologically active treatment, at least some of their side effects can be attributed to the placebo or in this case the nocebo effect, as well as given that many of these effects also occurred in the placebo group. Haas 'and colleagues' analysis indicated that nocebo accounted for 76 percent of all adverse reactions in the vaccine group and nearly a quarter of all reported local effects.

After the second dose, adverse reactions occurred in the placebo group to 32 percent who reported systemic events and 12 percent who reported local effects. In contrast, participants who received the vaccine reported more side effects, with 61 percent reporting systemic side effects and 73 percent reporting local side effects. The researchers estimated that nocebo accounted for almost 52 percent of the reported side effects after the second dose. Although the reason for this relative decrease in nocebo effects can not be confirmed, the researchers believe that the higher frequency of side effects in the vaccine group may have made the participants expect more more the second time.

"Nonspecific symptoms such as headaches and fatigue - which we have shown to be particularly nocebo-sensitive - are among the most common side effects after COVID-19 vaccination in many information leaflets," said senior author Ted J. Kaptchuk, director of the program at Placebo Studies and the Therapeutic Encounter at BIDMC and Professor of Medicine at Harvard Medical School. "Evidence suggests that this kind of information can cause people to mistakenly attribute common daily background sensations as arising from the vaccine or cause anxiety and worry that make people hyper aware of bodily feelings about unwanted events."

Kaptchuk and colleagues are known for a large and growing body of evidence showing that full detection of placebo treatment, what he calls "open label placebo", can actually improve common chronic conditions without any nocebo effects. While some researchers believe that informing patients about side effects can cause harm, Kaptchuk believes it is ethically necessary to fully inform participants about the potential side effects of the vaccines.

"Medicine is based on trust," Kaptchuk said. "Our findings lead us to suggest that informing the public about the potential for nocebo reactions may help reduce COVID-19 vaccination concerns, which may reduce vaccination hesitation."

Reference: "Frequency of adverse events in the placebo arms of COVID-19 vaccine trials" 18 January 2022, JAMA Network Open.

Co-authors included Sarah Ballou, PhD, and John Kelly, PhD from BIDMC; Friederike L. Bender, MS, Marcel Wilhelm, PhD, and Winfried Rief, PhD from Philipps University Marburg; and Franklin G. Miller PhD, from Weill Cornell Medical College.

This work was supported in part by a postdoctoral fellowship from the German Academic Exchange Service (Deutscher Akademischer Austauschdienst, DAAD) to Haas.

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