Placebos have been in use since antiquity and may have been significant in improving health and quality of life when little was known about the etiology of most illnesses. In fact, most outcomes were likely due to a placebo effect since the available treatments were unproven. For example, the use of snake oil and bloodletting was a common practice of the past. However, those that responded positively to those treatments likely did so because of a placebo effect. The emergence of placebo-controlled clinical trials in the 1940s reintroduced the placebo effect to the modern day. The classic article “The Powerful Placebo” by Henry Beecher highlighted the placebo effect and emphasized a need to account for it to evaluate the efficacy of a treatment modality properly. Both research and clinical settings utilize the placebo effect.
The placebo effect is a fascinating phenomenon that occurs when a sham medical intervention causes improvement in a patient's condition because of the factors associated with the patient’s perception of the intervention. Examples of placebo interventions include sugar pills, saline injections, and therapeutic rituals. Placebo effects are not limited to inert interventions. Proven effective treatments can also generate a placebo effect. Traditionally, the placebo effect was considered a nuisance variable to be controlled for; however, in light of some remarkable research demonstrating its potential to modulate treatment outcomes in recent decades, there has been a spiked interest in studying this phenomenon.
The placebo effect can be verbally induced or result from conditioning and prior experiences that shape patient expectations. Several research studies have demonstrated the placebo effect's role as a powerful determinant of health in certain disease conditions. Migraines, joint pain, arthritis, asthma, high blood pressure, and depression are some disease conditions that are more sensitive to the placebo effect. It is a complex phenomenon with several underlying psychological and neurobiological mechanisms. These underlying mechanisms that mediate placebo responses differ based on the medical condition and the investigated outcomes. Not all results of a placebo are beneficial, and as such, placebos can also result in undesirable outcomes. Indeed, the term "nocebo effect," derived from the Latin nocere meaning “harm,” is commonly used when a placebo causes an unfavorable outcome. Both placebo and nocebo effects have the same mechanisms, which are presumably psychogenic, but they can induce measurable changes in the body.
Mechanisms of Placebo Effect
Despite dramatic advances in scientific knowledge surrounding the placebo effect, efforts to characterize this phenomenon are in their primitive stages. The complex nature of mind-body interactions, supplemented by the negative connotations associated with placebo effects in the past, have hampered understanding of it. However, researchers are beginning to unravel the neurobiological basis of placebo effects. Classical conditioning and expectancy are two hypothesized psychological mechanisms known to mediate the placebo effect. Classical conditioning is a form of learning where an association is formed between a stimulus and a response. The association is then remembered, affecting future experiences. Through this process of association, patients may acquire a behavior. For example, a patient may report a decrease in pain after receiving a placebo pill that looks similar to pain medication that was previously effective in easing the pain. Whenever the same stimulus is encountered in the future, the patient conditions himself by shaping expectations and shows a previously imprinted response in his memory. Learning and adaptation, therefore, drive a conditioned response.
Expectations of the patient also play a vital role in mediating a placebo effect. Expectations can impact the course of treatment by affecting the psychological and physiological responses to that treatment. Along with classic conditioning, expectations can be induced by verbal instructions or social learning. For example, a research subject treated for pain with a placebo in the context of a verbal cue that the placebo is in an effective analgesic may shape his expectations and elicit an analgesic response. Conditioning and expectancy are often entangled mechanisms mediating placebo responses. Neurobiological mechanisms underlying the placebo effect are best characterized in placebo analgesia. In addition to these mechanisms, several other influential elements are at work during the placebo effect. These include the patient-physician relationship, the patient’s psychological state and personality, the severity of the medical condition, and environmental circumstances. The patient's genetics may also influence the degree of the placebo effect. Researchers are studying how genes can influence the placebo effect in various pathways, including dopamine, opioid, serotonin, and endocannabinoid systems. Evidence also indicates that the therapeutic benefits of the placebo effect may not impact the pathophysiology of the underlying disease being studied but rather address the subjective self-appraised symptoms of the disease. Elucidating the underlying mechanisms that mediate the placebo effect may prove beneficial to clinical practice and drug development.