Placebo, which is Latin for “I shall please,” is a simulated medical intervention that could produce an actual or perceived improvement, which, in turn, is called the “placebo effect.”

In medical research, placebos function as the control group in multiple designs of scientific experimental studies. They depend on the use of controlled and measured deception for their effect. Common forms of placebo include inert tablets, sham surgery, and the placement of random needles that convey false information to the patient.¹ Another example would be injecting saline or air into the epidural space. In a common placebo procedure, a patient is given an inert pill and told that it may improve his or her condition but not told that the pill is, in fact, inert. Such an intervention may cause the patient to believe that the treatment will change his or her condition, and this belief may in turn produce a subjective perception of a therapeutic effect, causing the patient to feel the condition has improved.

The placebo effect points to the importance of perception and how our central nervous system can produce a profound effect in the absence of any real external intervention. However, when used as treatment in clinical pain practice, the deception involved in the use of placebos creates a major dichotomy between the Hippocratic Oath and the honesty of the doctor-patient relationship.

The American Osteopathic Association² has published a position paper that specifically bans the use of placebo as part of therapy. Similarly, the United Kingdom Parliamentary Committee on Science and Technology³ has stated that “… prescribing placebos… usually relies on some degree of patient deception” and “prescribing pure placebos is bad medicine. Their effect is unreliable and unpredictable and cannot form the sole basis of any treatment in the National Health Service.”

The American Board of Anesthesiology Pain Management curriculum requires all pain practitioners to understand the role of placebo and nocebo in historical medical practice and their current use in clinical research.

The word placebo derives from a Latin translation of the Bible by St. Jerome,⁴ in Psalm 114: “I shall please the Lord in the land of the living.”

Placebos were first used in a medicinal context in the 18th century. In 1785, the New Medical Dictionary defined placebo as a “commonplace method or medicine.” Placebos were widespread in medicine until the 20th century, and they were sometimes endorsed as necessary deceptions. In 1903, Richard Clarke Cabot, MD, a professor at Harvard Medical School, said that he was brought up to use placebos, but he ultimately concluded by saying, “I have not yet
found any case in which a lie does not do more harm than good.” From this point onward, the use of placebos as part of a regular regimen of medicine rapidly declined.

In a landmark article, “The Powerful Placebo,” Henry Beecher, MD,⁵ the founding chair of the Department of Anesthesiology at Massachusetts General Hospital and Harvard Medical School, reviewed the placebo effect and its clinically important effects. He documented several dramatic effects in clinical trials. This view was notably challenged when, in 2001, a more systematic review⁶ of clinical trials concluded that there was no evidence of clinically important effects, except perhaps in the treatment of pain and some subjective outcomes. More recently, a Cochrane review on the use of placebos⁷ reached similar conclusions. Most studies have attributed the difference from baseline until the end of the trial to a placebo effect, but the recent reviewers have sought to examine studies that had both placebo and untreated groups, in order to distinguish the placebo effect from the natural progression of the disease. However, while placebo effects may be short lived, even some brief measure of pain relief can have some benefit for the patient.

A placebo has been defined as “a substance or procedure … that is objectively without specific therapeutic activity for the condition being treated.” Using this definition, a wide variety of things can be placebos and exhibit a placebo effect. Many substances administered through any means can act as placebos, including pills, lotions, creams, inhalants, and injections. Devices such as transcutaneous electrical nerve stimulation units and ultrasound machines can act as placebos, when placed in areas where no therapeutic effect is expected. Sham surgery and interventional procedures, sham intracranial electrodes, and sham acupuncture—either with sham needles or needles placed at nonacupuncture points—have all exhibited placebo effects. Even the presence of the physician, wearing a white coat within the patient’s room, has been considered as a placebo. This has been demonstrated in a study of patient recovery, in which the patient’s perceived recovery occurred sooner when the physician suggested that the patient “would be better in a few days.” The study also demonstrated recovery to happen sooner when the patient is given treatment and the physician tells the patient that “the treatment will certainly make you better,” rather than negative words such as “I am not sure that the treatment I am going to give you will have an effect.”

This placebo response phenomenon is related to the perception and expectations of the patient; if the substance is viewed as helpful, it can heal, but if it is viewed as harmful, it can cause negative effects, which is known as the nocebo effect (vide infra). The basic mechanisms of placebo effects have been investigated since 1978, when it was demonstrated that the opioid antagonist naloxone could block placebo painkillers,⁸ suggesting that the actions of endogenous opioids are involved.

Placebos exert an “expectancy” effect, whereby an inert substance that the patient thinks is a drug has effects similar to those of the actual drug. Placebos can act similarly through classical conditioning, where a placebo and an actual stimulus are used simultaneously until the placebo is associated with the effect from the stimulus. Both conditioning and expectations play roles in the placebo effect, and they make various types of contributions. Conditioning has a
longer-lasting effect, and it can influence earlier stages of information processing. The expectancy effect can be enhanced through factors such as the enthusiasm of the doctor, differences in size and color of placebo pills, or the use of other inventions such as injections. In a study,⁹ the response to a placebo increased from 44% to 62% when the doctor treated patients with “warmth, attention, and confidence.” Expectancy effects have been demonstrated to occur with a range of substances. Those who think that a treatment will work display a stronger placebo effect than those who do not, as evidenced in several studies of acupuncture.

Because the placebo effect is based on expectations and conditioning, the effect disappears if the patient is told that his or her expectations are unrealistic or that the placebo intervention is ineffective. A conditioned pain reduction can be totally removed when its existence is explained. For example, a placebo described as a muscle relaxant will cause muscle relaxation and, if described as the opposite, will result in increased muscle tension.

Because placebos are dependent upon perception and expectation, various factors that change the perception can increase the magnitude of the placebo response. For example, studies have demonstrated that the color and size of the placebo pill makes a difference, with “hot-colored” (eg, red, yellow) pills working better as stimulants, whereas “cool-colored” (eg, blue, purple) pills work better as depressants (Fig. 7.1). Capsules seem to be more effective than tablets, and size can make a difference. One group of researchers¹⁰ has demonstrated that bigger pills increase the effect, whereas others¹¹ have argued that the effect is dependent upon cultural background. If the physician is of the same social group as the patient and with whom the patient may share a common bond, a larger effect maybe demonstrated. More pills, branding, past experience with similar pills, and a higher price increase the effect of placebo pills. Injection and acupuncture seem to have a larger effect than pills.