How placebo and nocebo effects work

All physicians are familiar with what is called the placebo effect: the improvement in a patient’s symptoms after receiving a treatment that has no known effect on the particular disease. I was taught that statement could be further refined to state: improvement in a patient’s symptoms after receiving a treatment that has no known biological effect on the particular disease. The standard example is a “sugar pill.” That’s an important distinction, but it’s also clearly wrong; improvement in symptoms is obviously a biological effect, no matter the mechanism. The placebo effect is evidence of the complex interactions between mind and body because symptoms, by definition, are things perceived by the brain and cannot be specifically measured. Placebo effects are perception. They do not, for example, shrink tumors, cure asthma, or control diabetes.

The placebo effect is a key reason why, as much as possible (sometimes it isn’t), we study patient response to new treatments using a placebo arm in randomized, controlled trials. These are studies in which a patient is randomly chosen to receive either the new drug or something presumed biologically to have no effect on the particular disease. Neither the patient nor the investigator knows which one the patient is getting until after the trial is over. (Some trials compare a new treatment with an existing one — that’s a different topic.) The placebo effect is when a patient receiving the inert substance, the sugar pill, experiences an improvement. How big is the effect? Sometimes it can be as high as 30% of patients. This is why a placebo group is so important for studying disorders in which subjective symptoms are the essence of the disease, such as migraine headaches. There is no objective test one can do to assess improvement; it is all patient-reported.

How does the placebo effect work? There is a wonderful and highly understandable discussion of this in a recent edition of The New England Journal of Medicine. The article is only a couple of pages long and well worth a read. There is also a good podcast accompanying the piece. The bottom line is that clearly the placebo is not really an inert substance in the sense of doing nothing. It is doing something to the patient’s perception of symptoms, often by using known pathways of neurotransmitters in the brain. From the article:

Moreover, recent clinical research into placebo effects has provided compelling evidence that these effects are genuine biopsychosocial phenomena that represent more than simply spontaneous remission, normal symptom fluctuations, and regression to the mean.

The authors describe a fascinating example of how the placebo effect can play a role in a complex disorder like asthma. In asthma we can measure air flow as the patient breathes; that is, we can get an objective measure of how severe a patient’s problem is. The patient typically feels short of breath, and the degree of reduction of airflow correlates with that symptom. But feeling short of breath is a subjective thing. It comes from the brain. I have seen both patients in severe subjective distress with only modest reduction in airflow and patients surprisingly comfortable with very decreased objective numbers. There is a significant subjective component to asthma. This has been demonstrated by giving an placebo breathing treatment to an asthmatic and then showing that, as expected, there is no improvement in airflow. Yet the patient may experience an impressive improvement in perceived breathing symptoms.

There is also another side to the coin, what is called the nocebo effect.

 . . . the psychosocial factors that promote therapeutic placebo effects also have the potential to cause adverse consequences, known as nocebo effects. Not infrequently, patients perceive side effects of medications that are actually caused by anticipation of negative effects or heightened attentiveness to normal background discomforts of daily life in the context of a new therapeutic regimen.

Here is an example. Patients in randomized controlled trials do not know if they are receiving the placebo or not. But just in case they are receiving the real drug they are informed of possible side effects. Interestingly, 4 – 26% of patients in the placebo groups in such trials stop their participation because of these perceived adverse effects. This is the nocebo effect.

One of the most fascinating aspects of this is that there appear to be genetic predispositions among people for experiencing a placebo effect. This is an area of active research. The authors’ conclusion is a good one, I think:

Of course, placebo effects are modest as compared with the impressive results achieved by lifesaving surgery and powerful, well-targeted medications. Yet we believe such effects are at the core of what makes medicine a healing profession.

The placebo effect has always been a part of medicine. Patient’s perceptions of their physician’s compassion have long been known to be important. Really, until quite recently in medicine the placebo effect was all physicians had to offer. And it’s not a bad thing. I think it explains the modest improvements reported by some patients receiving a wide variety of what we call these days alternative therapies, such as homeopathy.

Anyway, the essay is a good review of this fascinating subject, and I recommend it to you.


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