Placebo

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The placebo effect (Latin placebo, "I shall please"), also known as non-specific effects and the subject-expectancy effect, is the phenomenon that a patient's symptoms can be alleviated by an otherwise ineffective treatment, since the individual expects or believes that it will work. Some people consider this to be a remarkable aspect of human physiology; others consider it to be an illusion arising from the way medical experiments were conducted.

In the opposite effect, a patient who disbelieves in a treatment may experience a worsening of symptoms. This nocebo effect (nocebo translates from Latin as "I shall harm") can be measured in the same way as the placebo effect, e.g., when members of a control group receiving an inert substance report a worsening of symptoms. The recipients of the inert substance may nullify the placebo effect intended by simply having a negative attitude towards the effectiveness of the substance prescribed, which often leads to a nocebo effect, which is not caused by the substance itself, but more the patient's mentality towards her or his ability to get well.

Placebo-controlled studies

Beecher (1955) reported that about a quarter of patients who were administered a placebo, e.g. against back pain, reported a relief or diminution of pain. Remarkably, not only did the patients report improvement, but the improvements themselves were often objectively measurable, and the same improvements were typically not observed in patients who did not receive the placebo.

Because of this effect, government regulatory agencies approve new drugs only after tests establish not only that patients respond to them, but also that their effect is greater than that of a placebo (by way of affecting more patients, by affecting responders more strongly or both). Such a test or clinical trial is called a placebo-controlled study. Because a doctor's belief in the value of a treatment can affect his or her behaviour, and thus what his or her patient believes, such trials are usually conducted in "double-blind" fashion: that is, not only are the patients made unaware when they are receiving a placebo, the doctors are made unaware too. Recently, it has even been shown that "mock" surgery can have similar effects, and so some surgical techniques must be studied with placebo controls (rarely double blind, for obvious reasons). To merit approval, the group receiving the experimental treatment must experience a greater benefit than the placebo group.

Nearly all studies conducted this way show some benefit in the placebo group. For example, Kahn published a meta-analysis of studies of investigational antidepressants and found a 30% reduction in suicide and attempted suicide in the placebo groups and a 40% reduction in the treated groups. However, studies generally do not include an untreated group, so determining the actual size of the placebo effect, compared to totally untreated patients, is difficult.

Notable placebo effect absences

In psychological treatment, two disorders are known to have very low placebo effects: schizophrenia, and obsessive compulsive disorder.

Placebo and pain

Careful studies have shown that the placebo effect can alleviate pain, although the effect is more pronounced with pre-existing pain than with experimentally-induced pain. People can be [Conditioning|conditioned]] to expect analgesia in certain situations. For example see Wager (2004). When those conditions are provided to the patient, the brain responds by generating a pattern of neural activity that produces objectively quantifiable analgesia.

Evans (2004) argues that the placebo effect works through a suppression of the acute phase response, and as a result does not work in medical conditions that do not feature this. The acute phase response consists of inflammation and sickness behaviour:

• Four classic signs of ‘inflammation’: tumor, rubor, calor and dolor – swelling, redness, heat and pain.
• Sickness behaviour: lethargy, apathy, loss of appetite and increased sensitivity to pain.

Placebo and depression

A brain-imaging study by Leuchter (2002) found that depressed patients who responded to the placebo effect showed changes in cerebral blood flow, which were different to the changes in brain function seen in patients who responded to anti-depressant medication. Other studies such as Khan (2000) argue that up to 75% of the effectiveness of anti-depressant medication is due to the placebo-effect rather than the treatment itself.

Endogenous Opiates

Endogenous opiates are chemicals produced by the brain that suppress pain and produce analgesia and a sense of well-being. Opium and drugs derived from it (opiates) produce their "highs" by triggering the same brain receptors used by natural opiates. Increased release of endogenous opiates like endorphin is associated with pleasant experiences like excercise (the runner's high) and sex. The placebo effect can be blocked by naloxone, a drug that blocks the effects of opiates, suggesting that the placebo effect may be partly due to the release of natural opiates.

Objective or subjective effects?

An alternate opinion attributes the false perception of a placebo effect to the fact that patients who have been given a placebo report improvement earlier and more eagerly in order to please and thank the care giver. These patients may even do this when there is no real physical improvement attained. One quoted figure is that about one third of patients improve on a placebo, but a recent study has called that number into question. Hróbjartsson and Götzsche reported in 2001 that the placebo effect is much smaller than previously thought, if it exists at all. The 30 percent figure derives from a paper by Henry Beecher, published in 1955 (H. Beecher, 1955). Beecher was one of the leading advocates of the need to evaluate treatments by means of double-blind trials and this helps to explain why it has been so widely quoted.

The Hróbjartsson & Götzsche study demonstrated that in many studies where a control group was used that did not get any treatment at all, the effects in the no-treatment group were almost equal to the effects in the placebo group for studies with binary outcomes (e.g. well treated or poorly treated). The authors concluded that the placebo effect does not have "powerful clinical effects," and conceded that placebos have "possible small benefits in studies with continuous subjective outcomes and for the treatment of pain." They therefore concluded that there was no justification for its use outside of clinical trials.

In a follow-up study in 2004, the same authors were able to confirm their previous results and concluded: "We found no evidence of a generally large effect of placebo interventions. A possible small effect on patient-reported continuous outcomes, especially pain, could not be clearly distinguished from bias".

If their conclusions are correct, the placebo effect is reduced to a subjective placebo illusion, while retaining its importance as a statistical research tool. As such it is imperative to use it in research, but unethical to use it in normal clinical treatment of patients.

These conclusions contradict what some would now consider to be a great deal of folklore that has evolved around the whole idea of the placebo effect. That folklore has evolved in a "research vacuum" of ignorance about the true nature of the placebo effect.

What is new about these conclusions is an emphasis on the key words "subjective" and "pain". This explains the well-established fact that the placebo effect is most "effective" in conditions where subjective factors are very prominent or significant parts of the problem. Some of these conditions are: headache, stomach ache, asthma, allergy, tension, and especially the most subjective of them all - pain, which is a significant part of most serious (and many mild) illnesses.

It also explains why there is no conclusive documentation for placebos causing significant healing effects in serious biological pathologies.

Practical implications and consequences

According to these findings, a placebo can make you think you are better, and even temporarily feel that you are better, but it can't actually make you any better. It will not cause any significant physiological change in a serious disease. In short, it will fool you (which is its intended function in double blind experiments).

To most scientists, these conclusions aren't revolutionary, since they have been using placebos in research for years, based on assumptions that this was the case. If they had believed otherwise, they would have been acting against better knowledge.

Much quackery achieves temporary "success" by a conscious or unconscious misuse of this placebo illusion. To the patient, such misuse of placebos can be expensive and ultimately fatal. To the quack, it will fool the patient long enough to keep the scam rolling.

Placebo control groups will continue to be a vital part of double blind clinical trials for the foreseeable future. Even if the placebo effect is not a useful method for treating illness, its effects are observed in clinical studies and are real enough to interfere with efforts to determine the usefullness of new drugs and therapeutic procedures, unless they are properly controlled for.

Confounders mistaken for placebo effect

Due to the difficulty in ascribing causation, many phenomena overlap with - and can thus mistakenly be included in - statistics on the placebo effect.

• Natural termination of the disease process.
• Cyclical presentation of the disease.
• Errant diagnosis or prognosis.
• Temporary improvement confused with cure.

Neurobiology of the placebo effect

• Nucleus accumbens

See also

• Hawthorne Effect
• Observer-expectancy effect

External links

• "Placebo Effect: Harnessing Your Mind's Power To Heal" ScienceDaily, 2003-12-31
• Desonie, Dana "The Placebo Effect: Real or Imagined?"
• The Placebo Effect at the Skeptic's Dictionary
• "Mystery Painkiller" at sciencentral.com (includes a short video.)

References

• Andrews G (2001) Placebo response in depression:bane to research boon to therapy. British journal of Psychiatry,178, 192-194. Full text
• Beecher, H. K. (1955) "The powerful placebo" Journal of the American Medical Association 159 pp.1602-1606 [Original article, most cited one, claiming a widespread placebo effect]
• Carroll, Robert Todd (2001?) The Placebo Effect Accessed on 2004-05-19. [Part of the Skeptics Dictionary. Useful categorization of possible types of mechanism for the placebo effect if it exists.]
• Dodes, John E. (2001?) The Mysterious Placebo Accessed on 2001-01-19. Originally published in the January/February 1997 issue of Skeptical Inquirer. A nice overview of the placebo effect and how it influences the study of alternative medicines.
• Evans, Dylan. The Placebo Effect: mind over matter in modern medicine 2004. HarperCollins (UK) / Oxford University Press (US)
• Evans M. Justified deception? The single blind placebo in drug research. Journal of Medical Ethics 26(3):188-193 (2000).
• Harrington, Anne, ed. The Placebo Effect: An Interdisciplinary Exploration. 1997. Cambridge: Harvard University Press. ISBN 067466984-X
• Hrobjartsson, Asbjorn; Gotzsche, Peter C. (2001) "Is the Placebo Powerless? An Analysis of Clinical Trials Comparing Placebo with No Treatment" New England Journal of Medicine 344 (21) May 2001 pp.1594-1602 [Meta-analysis, destroying most but not all of the belief that there is evidence for a placebo effect.]
• Kienle G. S., Kiene H. (1997) "The powerful placebo effect: fact or fiction?" Journal of Clinical Epidemiology. 50 (12) pp.1311-8. [Destroys Beecher's original article]
• McDonald C. J., Mazzuca S. A., McCabe G. P., Jr. "How much of the placebo 'effect' is really statistical regression?" Statistics in Medicine 2(4):417-27 (1983).
• Nordenberg, Tamar (2000) "The Healing Power of Placebos" FDA Consumer magazine
• Senn S. J. "How much of the placebo 'effect' is really statistical regression?" Statistics in Medicine 7(11):1203 (1988).
• Senn S. J. "A personal view of some controversies in allocating treatment to patients in clinical trials." Statistics in Medicine 14(24):2661-74 (1995).
• Senn S. J. "Are placebo run ins justified?" British Medical Journal 314(7088):1191-3 (1997).
• Senn S. J. "The Misunderstood Placebo." Applied Clinical Trials 10(5):40-46 (2001).
• Senn S. J. The ignoble lie [letter; comment]. Journal of Clinical Epidemiology 45(11):1338-40 (1992).
• Senn S. J. "Ethical considerations concerning treatment allocation in drug development trials" Statistical Methods in Medical Research 11 pp.403-411 (2002).
• Senn S. J. (2003) Dicing with death (CUP: Cambridge)
• Simon, Steve (2003) Ethics of a placebo group
• Zubieta et al. (2005) "Endogenous Opiates and the Placebo Effect" The Journal of Neuroscience 25(34) p.7754-7762