“I’m addicted to placebos. I could quit, but it wouldn’t matter.” – Steven Wright
Placebo controls are a mainstay of clinical research in medicine. They are one of the gold standard features of the iconic “double-blind, randomised, placebo-controlled clinical trial.” This is surely an affirmation of the potency of the mighty placebo effect, right? Not really!
Even if placebo effects are a myth, placebo controls would remain a powerful tool to improve the quality of clinical trials.
The Rise and Fall of the Placebo Effect
A placebo is an intervention intentionally devised to be devoid of a relevant physiologic effect. The apparent over-achievement of placebo groups in some studies has created the impression of a potent therapeutic response to these intentionally impotent interventions. This has been given the moniker “placebo effect.” This enigmatic effect has garnered a mythology as a powerful inert intervention; a mysterious “black box” with unexpected power.
More careful studies and more critical analysis of prior data has taken much of the mystery and potency out of the placebo effect. These investigations have opened the black box and identified more mundane influences, biases, and statistical artifacts masquerading as the placebo effect. After proper attribution of these factors, the placebo effect mostly vanishes. To the extent that the placebo effect exists at all, its power has been greatly diminished.
Self-reported outcomes like pain and anxiety are vulnerable to influences that are difficult to measure, and these subjective responses remain the last hiding place for the placebo effect. Mike Hall and Dave Hahn have discussed the rise and fall of the powerful placebo narrative in previous Skeptic articles.
If the placebo effect is mostly imaginary, why are clinical investigators obsessed with using placebo controls? And if future research continues to neuter the placebo effect, will placebo controls be abandoned?
Placebos and clinical trials
The value of placebo-controls in clinical trials has little to do with the placebo effect.
Not every research question in medicine is appropriate for a placebo-controlled trial, but for investigating the safety and efficacy of an experimental medication, it remains a favoured study design
The value of a control group
Say, for example, we want to test the effectiveness of our new drug, humbly called “Panacea” for condition X. We find 1000 patients with condition X and treat them with Panacea. At the end of the study our measurements of condition X are unchanged. Can we conclude that Panacea is ineffective for condition X? Maybe, maybe not. What if condition X is a relentlessly progressive condition, something like Amyotrophic Lateral Sclerosis (ALS). No change might be a therapeutic victory. On the other hand, what if condition X is self-limited and usually resolves spontaneously, something like singultus (hiccups!). In this case, no change in the condition might be an indication that panacea is actually making the condition worse.
In order to figure out if a treatment is having a positive or negative effect, we need some reference for comparison, a so-called “control group.” There are many possible comparison groups we could imagine. The ideal control group would be identical to the treatment group. There is no perfect control group, but when possible and practical, using a random process to sort the experimental and control group is the best that can be achieved. This process maximises the likelihood that the groups will be matched in important factors such as: age, gender, severity of disease, co-morbidities, etc.
Here is how a randomised trial works. Each potential subject is assessed for eligibility according to a set of pre-defined criteria. After a process of informed consent, each eligible subject is then enrolled into the study. They agree to be in the study without knowledge of their treatment group. Only then is the subject randomly assigned to be in the treatment or control group.
The value of a placebo control
Now that we have sorted subjects into treatment and control groups, what does a placebo control add? It is desirable that the only difference between the treatment group and the control groups is the experimental treatment itself.
Randomisation ensures that the treatment and control groups are as similar as possible when they begin the study. Placebo controls ensure that the treatment and control groups are as similar as possible during the conduct of the study.
Implicit in placebo control is the assumption that the subjects do not know if they are receiving the experimental treatment or the placebo…they are blinded to their group assignment. To the extent possible the investigator(s) are usually blinded to the subject treatment assignment, as well. Placebo controls are a necessary feature for the blinding of subjects and investigators.
The argument for “blinding”
Imagine that you are the subject in a clinical trial of an experimental drug. As part of the informed consent process, you have been educated about the potential benefits and the potential risks of the study drug. Now imagine that you know you are in the treatment group. You might be more optimistic about your prognosis. You might be more enthusiastic about participating in the study. You might be more likely to comply with study activities. You also might be more vigilant about potential side effects.
Imagine that you know that you are in the control group. You might be more concerned that your condition is worsening. You may be more likely to seek treatments outside the study protocol. You might be more likely to drop out of the study. You might be less likely to report mundane life events as side effects.
Investigators are not immune to these types of biases. If an investigator is aware of who is in the experimental group and the control group, it could influence the way they interact with subject, the way they collect data, and in decisions they make in the conduct of the study. It also increases the possibility that they could accidently “unblind” the patient.
These potential asymmetries between the experimental and control groups are known as “bias,” and can confound the results of the research. Placebo controls and blinding are attempts to minimise bias in the design, conduct, and analysis of clinical trials. Minimising bias is one of the key features of the scientific method.
Conclusion
The value of placebo controls in clinical trials is not an affirmation of the power of the placebo effect. Even if the placebo effect is eventually proven irrelevant, placebo controls will remain a mighty tool to minimise bias in clinical trials.
