The placebo is a crucial component of clinical trials. An active intervention, one that has a presumed biologic mechanism of action targeted to a malady, is tested against an inert agent, the placebo. Inert means it has no mechanism of action aimed at the malady being studied.
The classic description of a placebo is the “sugar pill” but any inert agent that can be completely confused with the active agent being tested may be used. For example in recent randomized clinical trials of a potentially active agent targeted against COVID-19 (Remdesivir), the placebo was water, given intravenously because the active agent was, also, given, intravenously.
The placebo is used in clinical trails when it is unclear if the active treatment being tested is helpful. Like the COVID-19 trial above, the theory was that the drug would advantage patients. To test this, researchers compared the new agent with a placebo. In the trial they found that the new agent did not clinically meaningfully advantage a patient any more than the placebo (water). Hence, the active agent does not work as intended. (Some readers will note that the Remdesivir trial was considered helpful in that some patients recovered more quickly, but there were problems with the study design making this assertion untenable, in my view.)
The reason a placebo was chosen for the Remdesivir trial was that there wasn’t a competing treatment to test against the new agent. It is unethical to use a placebo if there is another useful agent that can be used for the patient’s malady. For example, it would be unethical to test a medicine to lower blood pressure versus a placebo in a person with high blood pressure. There are other useful agents to lower blood pressure, and not using one of those to compare with a new agent would be wrong. So, despite their importance in clinical trials, there are situations, even, in clinical research when using a placebo is unethical.
To this point, I have discussed placebos in the research setting. In those, researchers have noted that some people getting the placebo improve. Nearly always, the improvement is in a “subjective” outcome. Subjective means that the outcomes are based on personal feelings, tastes or opinion, or the judgements of others. The outcomes are not usually, or ever, life/death, time to progression of illness, or objective measures of a patient’s function, the most important outcomes of research. These are important not only for their effects on our life’s experience, but they are more accurately measured, a prerequisite of research.
The apparent improvement in subjective outcomes has led some to believe that the placebo has some clear and definite mechanism to help patients. Remember, however, the placebo is a fake, it has no tangible ability to act on a patient’s behalf. So, how does the placebo work, if it does? Some suggest a mind-body effect, when just thinking you may be better leads to feeling that you are. Or more commonly, entering a trial brings expectations of being better. In my view, this belief that placebos work is misplaced (and hard to prove) as the placebo effect is more likely an aberrancy of the clinical trail situation, not the effect of the placebo, per se.
I will argue, even, that people in the placebo half of a clinical trial who improve are not really improved. They just say they are improved. They may be saying they are better due to their expectations, or to make the researchers happy. But there may be an even more compelling reason why they say they improve. If I am correct, then, the placebo effect is a figment, not a clinical effect of an inert agent.
There are at least four reasons why placebos should not be used outside the clinical trail situation, and, maybe not even in that context. First, there is no scientific basis to assert that a placebo has an effect. Second, the context of the use of the placebo in a clinical trial setting is impossible in the clinical care setting. Third, using a placebo in clinical care means you have to lie and lying is always wrong in medical care. Fourth, when a physician uses a placebo they are asserting superiority over a patient’s decision making power.
Point 1: Scientific basis of the placebo.
The scientific basis of the placebo-effect is unclear, and, I argue, can’t exist outside a trial. Here is the context of the clinical trial; patients enter trials with the expectation of getting one of two treatment options; active or inert. This is a key contextual issue; patients think they may get an active agent even when they may not. Hence, while the placebo is hidden from the participant, so is the active agent. Since any effect of the placebo must be made up in the minds of those getting the placebo, any response to the placebo may be nothing more than a hope that they got the active agent. After all, the patient knows that one treatment does not work and the other might, creating a unique mental conundrum. The conundrum, then, is that the placebo is a straw-man against an active treatment alternative, one with a potential tangible means of helping. Hence, the placebo effect is nothing more than an arbitrary result of the comparison with an active control arm. (It is difficult to imagine testing a placebo when the comparator must be another placebo. Imagine the clinical trial; you will be randomized to receive one or another placebo and we have no idea if either is helpful. What would be the placebo effect in this trial?)
Point 2: The placebo effect cannot transfer from the clinical trial to the clinical bedside.
The context imposed by a clinical trial will never occur in the clinical setting. So, the arbitrary effect of the imposed comparison will not occur in clinical practice. In clinical practice you must tell the patient that they are getting only one treatment, and that the treatment is an inert agent with no proposed mechanism of action against the patient’s malady. Once you tell the patient they are getting a placebo, the context changes. The patient is no longer able to hope for an active agent. A person who knows they are getting an inert agent will respond differently than in the clinical trial setting. Hence, there is no scientific way to know if placebos effect clinical care.
There is another important disclaimer in measuring the effect of a placebo; we only know what the patient says when outcomes are measured. We may not have objective measures of “better”. Hence, the placebo effect may not be real, justespoused. Calling an espoused effect, true, creates even more obfuscation.
Point 3. Placebos in clinical care are lies.
I saw a recent graphic listing numerous ways that companies attempt to manipulate our buying habits. It was a remarkable list of how to lie about the true prices of products. For instance, showing price on a red tag leads to more purchasing than when showing the same price on a blue tag. To use a placebo, you would either have to tell the patient that it is a placebo, that the red and blue tags mean the same things, or lie and show them only the red tag. Lying, however, cannot be justified in the practice of medicine. Also, since we can’t know if placebos are beneficial, and, hence, that they may be nothing more than a means of manipulating a patient to espouse an effect, we must even lie to ourselves to use them.
Point 4: Placebos are machinations from a position of power.
Physicians using a placebo without disclosure to a patient in order to get a presumed effect, no matter how well-intentioned, must believe that they have the power to affect a change in a patient’s outcome that is greater than the patient’s innate ability to affect change. The placebo, then, is being used as an extension of the physician’s control.
The physician’s job, however, is to hand over control to a patient and to teach people who are ill to use their innate abilities to advantage themselves when faced with choices for care. Physicians are supposed to teach people to know good information from bad. Physicians are supposed to give scientific information on marginal benefits and harms of competing options for care so patients can make their own trade-offs. But, competing options only exist if they offer something proven in scientific experiments. Placebos fail on scientific grounds, alone.
The following statement is from the AMA guide on placebos, “The use of placebo, when consistent with good medical care …”. How can anything that lacks a scientific foundation, that is not able to be used in clinical medicine, that is a lie, and that is used as an extension of a physician’s power over a patient’s be consistent with good medical care? The physician visit is supposed to be the place to come for scientific information on the consequences of choices. The placebo does not fit in this job description. Using them makes the physician more a “medicine man” than a medical professional. Using a placebo means the physician has stepped away from their role as a truth teller for patients.
The AMA guide is wrong. There is no ability of the placebo to be consistent with good medical care; in fact, its use does just the opposite. They should not be used, they should, then, never need to be paid for. It is time to rethink placebos (even surgical shams) in clinical medicine
