The "Placebo Effect"

What is a Placebo?

The word dates to the fourteenth century. It is Latin for "I shall please". Reviews report that Hooper’s Medical Dictionary in 1811 defined "placebo" as: “an epithet given to any medicine adopted to please rather than to benefit the patient.”

The mid-twentieth century saw the development of many pharmaceuticals. Scientists needed a reliable way to differentiate the effects of these drugs from the natural history of disease and other confounding factors. In 1945, Pepper et. al published A note on the placebo in the American Journal of Pharmacy (117:409-412) describing the use of inert substances as controls for testing medications.

Since 1945, pills that contain no active drug have come to be known as "placebos". Specifically, the American Medical Association uses the definition: "A placebo is a substance provided to a patient that the physician believes has no specific pharmacological effect upon the condition being treated." They are usually made of sugar, thus the term 'sugar pill' has become synonymous with 'placebo'. Ideally, a medical researcher wants to control for all factors that patients experience in a research study, including the act of taking a pill. By using a fake drug - without the patient's full knowledge - in the control group, the effects of the actual drug in the treatment group can be measured.

Placebos are properly used in research. Placebos do not have to be pills. They can be inert injections made to appear like true injectable medications. They can be fake procedures, such as a superficial incision with stitches placed under anesthesia to mimic a surgery. Recently, placebo needles have been devised to simulate the actual placement of acupuncture needles. In short, placebos are fake treatments used to research the effectiveness of 'actual' treatments.

What is the "Placebo Effect"?

Before long, scientists began to postulate that patients were perceiving changes in symptoms in response to these inert placebos. In 1953, Beecher et. al were studying the effects of pain relievers. They used placebos in their control groups. Some of the control patients exhibited significant pain relief. The researchers called such patients "placebo reactors".

After removing the "placebo reactors" from the study, the researchers could actually measure a difference between the treatment and the control groups. So it seems that some patients - but not all - can experience pain relief with inert sugar pills comparable to narcotics.

In 1955, H.K. Beecher published a paper in JAMA called The Powerful Placebo. He concluded that up to 35% of the perceived effect of a treatment may be due to the placebo effect.

Since then, many have observed effects - presumably from placebos - in studies designed to test treatments for asthma, depression, anxiety, pain, high blood pressure and others. The effect resulting from taking a placebo is known as the "placebo effect". Moerman and Jonas pointed out that this is a bit of a circular definition, and is thus without substance. Yet, a significant percentage of patients seem to persist in feeling better after taking inert treatments, as long as they think that they are real.

The term "placebo effect" is often misunderstood. In terms of pain, there may be a physiologic response to the psychological thought of taking a treatment. Mostly, the "effect" is limited to subjective improvements rather than objective measures of disease improvements. Sometimes, the "effect" is not an effect at all, but rather the natural course of disease and symptoms.

Peter Lipson, MD, described it this way: "What we've learned about so-called placebos over the years is that "placebo" is not an intervention like a medication or a surgery. It is an artifact of observation. A certain amount of change can be expected any time you study a group of people. "Placebo (effect)" is simply all of the change that can't be explained by the primary intervention".

Is it Real?

Is it real? Well, it depends on what one means. A systematic review of the literature in 2001 suggested that placebos have not been found to produce measurable effects, with the possible exception of pain management.

Self-limited conditions, such as the common cold and acute back pain, progress over time with respect to symptoms in recognized patterns. After onset, symptoms reach a peak and then decline back to baseline. It is reasonable to expect that patients will seek care at or near the peak of symptoms. At that point, any advice or "treatment" will appear to work as the symptoms decline. Here, the perceived effect is attributed to the timing of a therapeutic action and the natural progression of a condition.

For instance, then natural history of a common cold is to worsen for 3 to 4 days, then slowly improve. Any intervention given at the peak of the symptoms will be perceived as therapeutic because the symptoms naturally begin to improve after the intervention. This is why many patients insist that the antibiotic they took always "nips my cold in the bud".

When studies are done to investigate such treatments, they must be compared to a placebo "treatment" to determine if the effect is real. If the improvement in the treatment arm in the study is not superior to the improvement in the placebo arm, then the treatment is deemed ineffective. The perceived effectiveness of the treatment is often called "the placebo effect". However, this is simply the natural progression of the condition and an incorrect assumption on the part of the practitioner and the patient.

Ernst then points out that it follows that if a treatment has a true effect - beyond any placebo effect - then it must be above and beyond the entire perceived placebo effect.

True placebo effects seem to mainly be present in treatments for subjective conditions such as pain, fatigue, depression and anxiety.

Oxytocin (the "love hormone") may be a major player in true placebo effects. Oxytocin is a hormone that is released from the pituitary gland during empathetic and emotionally engaging interactions between people. It is speculated that oxytocin is released during empathetic interactions between a caregiver and a patient. It is fair to speculate that interactions that are perceived as warmer and more caring (especially those involving the caregiver putting the patient in a relaxed setting and touching the patient in some way) may lead to higher oxytocin release from the patient's pituitary gland.

A 2013 study in JAMA demonstrated that intranasal oxytocin, when given with a sham pain reliever, led to a statistically significant increase in the perception of pain relief from the intervention. The study was well controlled to rule out a possible direct analgesic effect from the oxytocin itself. This likely does not explain the whole story, but it provides at least one possible biochemical pathway to explain true placebo effects.

Different Effects for Different Placebos

John Byrne, M.D.