Placebo
Adequately defining placebo is challenging. Any treatment or intervention can have both specific effects and non-specific effects.
- The specific effects are due to known physiological mechanisms.
- The non-specific effects are a paradox and are due to unknown mechanisms. The paradox is resolved if the unknown mechanisms of the nonspecific effects become known.
Any treatment effect that is not due to the specific, intended effects of a treatment is referred to as the placebo effect, and any beneficial effect that is not due to the specific intended effects is the placebo response.
The total effect of an intervention may be a combination of both its physiological known specific effects, and unknown non-specific placebo effect. An absolute placebo effect is when the intervention has no known therapeutic physiological effect or an intervention that is designed to simulate medical therapy but doesn't have a specific therapeutic effect. The opposite of a placebo effect is a nocebo effect, where harm occurs for non-specific unknown reasons.
Comparison with Other Effects
The placebo effect is a specific phenomenon that is sometimes confused with other effects.
Natural history: some conditions naturally improve over time because of healing or some other factor. The improvement in pain is a property of the disorder that the patient has not the placebo effect. These two effects are distinguished through comparing the outcomes of patients taking placebo and the outcomes of patients having no treatment.
Regression to the mean: This is a statistical phenomenon. Patients with chronic pain may be more likely to present to a doctor and join a trial when their pain is on the more severe end of what they have been experiencing to date. Conversely, patients who are doing well compared to their average are less likely to present to doctors and enrol in trials. There is therefore an overrepresentation of patients who are in a severe period of their naturally fluctuating pain levels. Measurements of pain and function may not represent their normal state, but the state of their flare. Regression to the mean refers to the statistical phenomenon that on average their pain is likely to improve to their previous average level of pain, regardless of treatment. This is not a placebo effect, but simply reflects normal fluctuations in pain.
Hawthorne effect: When individuals are being observed there is a change in performance simply because they know they are being studied. This is a conscious or subconscious change.
Mechanism
There are four main theories regarding the mechanism of the placebo effect.
Classic Conditioning: The placebo response is a conditioned response to features of the treatment setting such as the doctor's style of dress, equipment, medication. Relief occurs because of past experiences of having relief from going to the doctor.
Response Expectancy Theory: The placebo response is due to an expectation from the patient that it will relieve their pain.
Meaning Model: The patient is listened to and has received a valid coherent explanation for their illness, the patient feels care and compassion from the doctor, and the patient feels empowered. By having these three factors, any fears are reduced and pain and function may improve simply as a result of that.
Cognitive Dissonance Theory: The patient avoids holding two psychologically inconsistent beliefs: that the treatment would work and only very sick people don't improve. To reduce this dissonance the patient alters their perception of their symptoms.
Biochemical Mediators
The evidence is compelling that the placebo effect is a biochemical not a psychological phenomenon.
Endogenous opioids are involved. The placebo effect is reversed by naloxone. It is enhanced by antagonism of cholecystokinin receptors. Placebo analgesia can mimic the respiratory depression side effect seen with exogenous opioids, and this side effect is reversible with naloxone.
There is also some evidence that catecholamines and cortisol are involved.
Response Rate
A commonly quoted figure is that 35% is the standard incidence of placebo response rates. However this figure, published in 1955, was the average placebo responses in 15 papers.[1] In fact, the incidence of placebo response varies between 0 and 100% depending on the disease, environment, investigator, and other factors. Furthermore, a particular individual can be both a placebo responder and a placebo non-responder under different settings.[2][3]
- ↑ BEECHER HK. The powerful placebo. J Am Med Assoc. 1955 Dec 24;159(17):1602-6. doi: 10.1001/jama.1955.02960340022006. PMID: 13271123.
- ↑ Voudouris NJ, Peck CL, Coleman G. Conditioned response models of placebo phenomena: further support. Pain. 1989 Jul;38(1):109-116. doi: 10.1016/0304-3959(89)90080-8. PMID: 2780058.
- ↑ Peck C, Coleman G. Implications of placebo theory for clinical research and practice in pain management. Theor Med. 1991 Sep;12(3):247-70. doi: 10.1007/BF00489609. PMID: 1721730.
