Tag Archives: Research

Covid-19 Vaccines a ‘nocebo effect’ …?

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Meta research (an aggregation and analysis of related research efforts) has revealed a curious ‘nocebo effect’ related to reaction to Covid-19 vaccinations.

” … Researchers at Harvard Medical School and Beth Israel Deaconess Medical Center compared the rates of adverse events reported by participants who received the vaccines to the rates of adverse events reported by those who received a placebo injection containing no vaccine.

Although the scientists found significantly more trial participants who received the vaccine reported adverse events, nearly a third of participants who received the placebo also reported at least one adverse event, with headache and fatigue being the most common.”

The placebo value-add

A placebo might be given as a stand-alone remedy, or as recent research claims, given as an augmentation to another remedy, adding value to its effect while introducing no extra chemical agent in the process. Just the influence of expectation and will.

The prestigious journal Nature, has published this study – Harnessing the placebo effect to enhance emotion regulation effectiveness and choice

“… There is extensive placebo literature showing how forming positive expectancies can augment the effectiveness of already effective treatments. In that sense, placebo effects are not limited to inert treatments, but also represent a powerful mechanism for boosting outcomes following the administration of active treatments.”

The placebo effect and AI!

It seems the placebo effect is ubiquitous. With all the recent excitement and ocnjecture about rapid advances in Artifical Intelligence and Machine Learning, it seems that our belief that a decision is backed by an AI will not only enhance our confidence in the veracity of that decision, but also make for better decisions! This research shows that:

“Participants were asked to solve word puzzles while being supported by no system or an adaptive AI interface. All participants experienced the same word puzzle difficulty and had no support from an AI throughout the experiments. Our results showed that the belief of receiving adaptive AI support increases expectations regarding the participant’s own task performance, sustained after interaction. These expectations were positively correlated to performance, as indicated by the number of solved word puzzles.”

The Ritual of Treatment

A good updated report on the placebo effect in clinical settings – Placebos Demonstrate Power of the Human Mind

Professor Ted Kaptchuk, who studies the effect, explains:

“The placebo effect is more than positive thinking — believing a treatment or procedure will work. It’s about creating a stronger connection between the brain and body and how they work together” …

Placebos won’t, for example, cure cancer. But when a disease affects the brain-body relationship, as Angelman does, the placebo response can confound research, as we saw above. We learn from the National Library of Medicine that “Migraines, joint pain, arthritis, asthma, high blood pressure, and depression are some disease conditions that are more sensitive to the placebo effect.”

More on Nocebos and Vaccine Side Effects

Further to our most recent post about the likelihood that the frequency of adverse side effects may be attributable to the placebo effect (or more appropriately, the nocebo effect), here’s some more detail provided by reknowned placebo research Ted Kaptchuk, in an article from the Harvard Medical School, ‘Power of Placebo: Some COVID-19 vaccine reactions may result from placebo response’.

“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 senior author Ted Kaptchuk, HMS professor of medicine and director of the Program in Placebo Studies at Beth Israel Deaconess.

“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 hyperalert to bodily feelings about adverse events,” he said.

Kaptchuk and colleagues are known for a large and growing body of evidence showing that full disclosure of placebo treatment, what he calls “open-label placebo,” can actually improve common chronic conditions without any nocebo effects. Kaptchuk believes it is ethically necessary to fully inform participants about the vaccines’ potential adverse reactions.

“Medicine is based on trust,” said 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.”

Did you know these three facts about the placebo effect?

You may be surprised to read of three ‘effects’ of placebos proposed recently by Eve M. Krakow in Psychology Today.

Dr Krakow takes pains to emphaise that the placebo effect is a physical phenomenon. There’s nothing magical about it. It will seem magical (as Isaac Asimov once wryly observed) until there’s sufficient science.

First, the placebo has a negative ‘flipside’. This is the nocebo effect, and it’s noted and discussed elsewhere on this site (check the tags column). A placebo effect can have either positive or negative outcomes.

Second, and very weirdly (if not ‘magically’) the placebo effect seems to become stronger and more proncounced over time. Placebos seem to get stronger!

Thirdly, the placebo effect does not necessarily require deception – that is, the practitioner lying to a patient that the (inert placebo) treatment is actually the ‘real’ treatment. We cover this too, on this site – look for ‘white label placebos’ in the tags.

Vaccine side effects are nocebos?

One of the anti-vax memes in circulation is the risk of side effects from Covid vaccines.

meta-analysis of 12 randomized, placebo-controlled clinical trials, a team of researchers at Beth Israel Deaconess Medical Center (BIDMC) in Boston found that up to 64 percent of adverse effects may be attributable to this kind of worry. See this article in Science Alert.

Interestingly, the meta-analysis engaged with the ‘placebo effect’ as a nocebo effect, with (across the 12 trials) about half of participants taking the vaccine, the other half a placebo. The nocebo effect accounted for up to 76 percent of systemic adverse events and 24 percent of local adverse events after the first vaccine dose.

We’re unsurprised to read that non-specific symptoms (think pain, mood disorder, IBS) are particularly ‘nocebo sensitive’.

Placebos getting ‘STRONGER’?

Analyzing the results of 84 clinical trials conducted between 1990 and 2013 exploring drugs to treat neuropathic pain, researchers found that the placebo effect actually grew stronger over that time, but only in the U.S. In other words, placebo pills given in 2013 seemed to reduce American patients’ self-reported pain much more than they did in the 1990s.

A strengthening placebo effect has also been seen in trials for psychiatric drugs. And this has genuine consequences. Fewer pharmaceuticals are being approved because they can’t contend with the rising placebo effect.

So what is going on?

The evolution of placebo studies

There is now a Society for Interdisciplinary Placebo Studies.

“Our mission is to promote communication and cooperation between research centers and scholars in order to facilitate rapid dissemination of research results and theoretical ideas concerning placebo studies. Our goals are to use multidisciplinary tools (neuroscience, psychology, cognitive science, history, anthropology, and philosophy) to examine the physiological and psychological mechanisms underlying placebo effects, and to develop ethically acceptable methods to harness the placebo effect to improve treatment outcomes.”

Our experience in the commercial arena, which incidentally keeps us abreast of developments in understandings of the placebo effect. has seen a shift from ‘crackpot fringe’ to ‘scholastic fringe’ in the direction, we hope, of acceptance of placebo studies as a legitimate field of research, grounded in a real phenomenon

Using placebos in Covid trials

Prestigious British journal The Lancet has addressed ethical concerns related to using placebo controls in trials of Covid remedies and vaccines, finally arguing in favour of there use. The full article, dated February 19, 2021, is quoted below.

“The COVID-19 pandemic has affected our world like no other virus or disease in the past century. Thus, having a reliable vaccine to prevent its spread is urgent. The scientific community and society received with great hope the issuance of two COVID-19 vaccines by the US Food and Drug Administration for Emergency Use Authorization (EUA). However, this milestone has brought ethical and methodological questions about the continued use of placebo control for new candidate vaccine trials.

In January, 2021, our institutional review board approved an application for a phase 3, placebo-controlled COVID-19 trial using a protein-based platform in Ecuador. Here we share our experience and the rationale used to approve this protocol. The following are the justifying elements used in our judgment.

First, we had to consider economic and logistical issues. A proposed strategy to evaluate COVID-19 vaccines after EUA is to run head-to-head randomised trials with non-inferiority designs.

Due to an international shortage of approved vaccines, it is not feasible to do this kind of design locally. This constraint is even worse for low-income and middle-income countries (LMICs), which have less capacity to negotiate and purchase vaccines than do high-income countries (appendix). For example, by Feb 12, 2021, Ecuador was able to acquire 8000 doses of the Pfizer–BioNTech vaccine; however, there is a lot of uncertainty as to when and how many doses we will receive throughout the year to continue our massive vaccination programme.

Second, there is room to claim clinical equipoise in COVID-19 vaccine trials. Although we acknowledge the rigorous development process and comprehensive evaluation that the two vaccines faced to be granted EUA, they are still not completely licensed medical products and are subject to long-term surveillance, especially for safety. The scientific literature shows examples of fully licensed vaccines that have had to be taken off the market due to safety concerns (eg, Rotavirus vaccine).

Third, some scientists and bioethicists argue that researchers doing clinical trials should treat participants as if they were patients. If that is the case, in the best of their clinical interests, it would be unethical to give the participants a placebo.

We disagree with this argument and recognise that the researcher’s obligations differ among participants and patients. After our institutional review board assessed the risk–benefit profile of the new candidate vaccine and concluded that the benefits outweigh the potential risks, we concluded that use of proper informed consent would allow participants to enrol in the trial and accept some risks to collect socially valuable data.2
Having multiple vaccine producers to overcome this global shortage scenario is morally and ethically imperative, especially for LMICs.

We declare no competing interests.”