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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.”

The placebo effect in pain science

It may be that the placebo effect is ‘not all in your head’. Findings from a new study indicate distinct physiological effects related to the perception of pain, according to a patient’s belief that a cream applied to their arm was either generating heat (the ‘nocebo’ option), numbness (the ‘placebo’ option) or no change (the ‘control’). All of the ‘creams’ were actually Vaseline. (Ref. Brainstem mechanisms of pain modulation: a within-subjects 7T fMRI study of Placebo Analgesic and Nocebo Hyperalgesic Responses, The Journal of Neuroscience)

The Australian researchers measured brainstem activity with high-resolution functional MRI (fMRI) in participants as they rated the pain of a hot stimulus applied to their arm.

From this article: “Over two successive days, through blinded application of altered thermal stimuli, participants were deceptively conditioned to believe that two inert creams labeled ‘lidocaine’ (placebo) and ‘capsaicin’ (nocebo) were acting to modulate their pain relative to a third ‘Vaseline’ (control) cream.”

Placebo and nocebo effects influenced activity in the same brainstem circuit but in opposite ways. The strength of the placebo effect was linked to increased activity in an area called the rostral ventromedial medulla and decreased activity in a nucleus called the periaqueductal gray; the nocebo effect induced the opposite change. These results reveal the role of the brainstem in pain modulation and may offer a route for future treatments of chronic pain.

“Placebo and nocebo effects influenced activity in the same brainstem circuit but in opposite ways. The strength of the placebo effect was linked to increased activity in an area called the rostral ventromedial medulla and decreased activity in a nucleus called the periaqueductal gray; the nocebo effect induced the opposite change. These results reveal the role of the brainstem in pain modulation and may offer a route for future treatments of chronic pain.”

Placebo Effect Beer

Well, somebody bit the bullet and came clean with their claims for a non-alcoholic beer: it’s a placebo! Yes, Placebo Beer is now on tap in Houston, Texas.

“Angela, one of our brewers here at Urban South, is the mastermind behind this new series,” said Dave Ohemer, General Manager of Urban South – HTX. “We noticed an increasing number of our guests were non-alcohol drinkers who still wanted to visit the brewery with friends and family for the atmosphere or to enjoy some of our local food options. Our brewing team is excited for the opportunity to experiment with some of the ingredients we use in our fruited sours and create an option for this growing audience. We’ve received great feedback so far and look forward to continuing to develop the Placebo Effect series.”

Microdosing with Psychedelics

Micro-dosing psychedelics as a therapy and productivity booster is all the rage in some quarters (like Silicon Valley). But is that a placebo effect?

People may not have to microdose psychedelics to feel their wellbeing benefits, according to a new study – they just have to believe (our italics) they’ve microdosed them.

Published in eLife, the new study found that participants who took placebos often reported the same beneficial effects as those that actually microdosed psychedelic substances. Likewise, those who believed they had taken a placebo, even when they had actually taken a psychedelic drug, experienced fewer improvements to their wellbeing.

Given these findings, the researchers suggest that the anecdotal benefits of microdosing can be explained by the placebo effect.

The Virus and the Placebo

The placebo effect will have to be taken into account in the development of vaccines and treatments, according to this opinion in Stat News.

“The placebo response is a complex psychobiological phenomenon that describes the clinical improvement seen in patients taking dummy or sham medicines. It can also comprise some proportion of the measured effect among patients receiving active drugs. Multiple behavioral, psychophysiological, and neuroimaging studies have shown that the placebo response is a real, multifactorial effect associated with changes in biochemical pathways in the brain. The effect is patient specific and is influenced by patient expectations and certain well-defined personality traits.

While drug developers are attuned to considering the placebo response in areas like pain and depression, it may not be immediately apparent why it is so critical for the development of Covid-19 therapies and vaccines. What set the stage was the FDA’s regulatory guidance, released in May, directing how the biopharma industry should evaluate drugs and vaccines being developed to fight the pandemic.”

What’s in a placebo?

When is a placebo not a placebo? It seems that placebos are no as ‘unreactive’ as the literature would suggest. Research hastened and made more urgent by the rushed efforts to develop a Covid-19 vaccine have revealed the need to create a standard for the actual content/ingredients of the placebo used in a given trial.

This article claims that:

“Some researchers conducting clinical trials on a COVID-19 vaccine have not revealed to the public what the placebo contains, but they should. This is because the placebo ingredients influence how effective or harmful the active treatment, with which the placebo is compared, appears.”

Later, the article continues:

“Placebo controls are rightly the gold standard against which new treatments are measured. If a new treatment proves to be better than a placebo, it is taken to be effective. Otherwise, it isn’t. The problem is that until today, there has been no standard for placebos, which made estimates of side-effects confusing. Our new guideline fixes this problem by encouraging rigorous reporting of placebo ingredients.

We’ve known about the failure – and need – to report what’s in placebos for 15 years. By following the new guideline, we can get more accurate information about how beneficial and harmful treatments tested in placebo-controlled trials are.”

Here’s a study on ‘A guide and checklist for reporting placebo and sham controls’

Using placebos in a Covid 19 vaccine?

In this article the author argues strongly against using the ‘double blind placebo controlled’ methodology in testing the effectiveness of the numerous vaccines now in the works.

” … the use of a placebo in a challenge trial for a Covid-19 vaccine is both pointless and ethically questionable.

We’ll use a deliberately simplistic analogy to help explain why. Suppose we need to test a new type of parachute during wartime, when a better parachute happens to be urgently needed. Sooner or later it will have to be tried in a real jump. But we won’t let that happen until we are already quite sure it is going to work. And we are certainly not going to give dummy parachutes to a control group, randomly selected from a group of volunteers. We already know what will happen to them.”

While this logic may hold, as far as testing vaccines go, but we wonder if there’s space to think that, at least for symptoms if not the condition itself, placebos might have a place? After all, nobody yet understands how an intangible input like a placebo actually seems to cause real effects in the material world …