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.
“… 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.”
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.”
“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.”
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.
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.
It seems that this damned placebo effect is getting in the way of developing and authorising new psychiatric drugs. It creates a ‘therapeutic bias'(!) and so the experimenters are experimenting with ways of controlling for it in trials, for example ‘SPCD, sequential parallel comparison design’. These are proving to be not (yet) up to the task, sufficient to be acceptable by bodies such as the RDA. The following is from The Placebo Effect Is Hobbling New Psychiatric Drugs
“The FDA’s rejection cast doubt upon the design, still in use in more than a dozen trials, as a weapon against the placebo effect.
That’s big news because the effect, also called the placebo response, has been growing stronger over the years in clinical studies that randomly assign patients to either an active drug or placebo. When the effect is high, it’s hard to know if a drug just isn’t good enough, if there are errors in the data, or if the participants taking the placebo—an inert pill meant to make them believe they’re getting the real thing—fared unusually well because of their expectations.
It’s a testament to the power of our minds to improve our health, at least temporarily. Many factors boost placebo response. “Most people, whether they know it or not, are biased to believe that they will receive the active drug even if they are told that they have a 50 percent chance of getting placebo, and this ‘therapeutic bias’ increases the placebo response,” says John Krystal, the chair of the psychiatric department at the Yale School of Medicine in New Haven, CT.”
What is now emerging as ‘placebo science’ has its roots in an influential 1955 paper entitled ‘The Powerful Placebo’ by Henry K. Beecher which proposed that placebo effects were clinically important. This remains the most commonly-cited placebo reference.
Henry Knowles Beecher (February 4, 1904 – July 25, 1976) was a pioneering American anesthesiologist, medical ethicist, and investigator of the placebo effect at Harvard Medical School, which now, fittingly enough, co-convenes the Program in Placebo Studies & Therapeutic Encounter (PiPS) with the Beth Israel Deaconess Medical Center.
The prestigious Beecher Prize, named in his honor, is awarded annually by Harvard Medical School to a medical student who has produced exceptional work in the field of medical ethics.
We all know about the ‘nocebo’ effect by now – the dark twin of the beneficial placebo effect. For example, a study showed that the pharmacological efficacy of remifentanil (a pain medication) was significantly decreased after patients were told the infusion was stopped during a heat-pain modulation test. Although the infusion had not actually been halted, participants experienced a significant exacerbation of pain even while still receiving remifentanil.
To counter undesirable ‘nocebo’ effects, this article suggests to health practitioners that ‘pragmatic strategies related to patient–practitioner interaction, clinical setting, and context may be implemented to help minimize and prevent the consolidation of negative expectations’.
What you expect is often what you get, and the placebo effect is at work! We have noted elsewhere that one possible account for the engagement of the placebo effect is the wish to ‘please the physician’, to be a ‘good patient’. According to this Stanford study, this might come as only a few positive words. “… When a health care provider offers a few encouraging words about their patient’s recovery time from an allergic reaction, symptoms are significantly reduced.”
Similarly expectations about the benefit of exercise can be seen to actually impact on life expectancy outcomes. In this study “the team looked at death rates. They used statistical models to account for other factors linked to death, such as age, chronic illnesses, and body mass index (BMI). Even accounting for these risk factors, those who saw themselves as less physically active were 71% more likely to die in the 21 years following the original survey.”
It is becoming increasingly clear that the placebo effect has a great influence on medical treatment. An international, interdisciplinary team of researchers led by Professor of Health Psychology Andrea Evers from Leiden University has now written a first set of guidelines on how to apply the placebo effect in clinical practice, published in Psychotherapy and Psychosomatics.
It was the result of the first official conference of the Society for Interdisciplinary Placebo Studies (SIPS), which was held in Leiden last year. During an interdisciplinary workshop led by Evers, a group of leading international researchers reached the consensus that knowledge about placebo and nocebo effects could lead to better treatment results with fewer side-effects. According to the researchers, it is crucial that patients receive more information about these effects, and that doctors receive training on the best doctor-patient communication to maximise placebo effects and minimise nocebo effects.