Placebo effect

The placebo effect (Latin placebo, "I shall please"), first mentioned in 1955 by Henry K. Beecher, M.D. (Beecher 1955) and 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. The phenomenon, if it exists at all, is not fully understood by science.(New Scientist Space 19 March 2005)

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, Khan 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. (Khan 2000) 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 conditioned to expect analgesia in certain situations. When those conditions are provided to the patient, the brain responds by generating a pattern of neural activity that produces objectively quantifiable analgesia. (Benedetti 2003, Wager 2004)

Evans argued 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. (Evans 2005) 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 found that depressed patients who responded to the placebo effect showed changes in cerebral blood flow, which were similar to the changes in brain function seen in patients who responded to anti-depressant medication. (Leuchter 2002) Other studies argue that up to 75% of the effectiveness of anti-depressant medication is due to the placebo-effect rather than the treatment itself. (Khan 2000)

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 exercise (the runner's high) and sex. When patients who claimed to experience pain relief after receiving a placebo were injected with naloxone (a drug that blocks the effects of opiates), their pain returned, suggesting that the placebo effect may be partly due to the release of natural opiates. (Sauro 2005)

Objective or subjective effects?

Hróbjartsson and Götzsche published a study in 2001 and a followup study in 2004 questioning the nature of the placebo effect. (Hrobjartsson 2001, Hrobjartsson 2004) They performed two meta-analyses involving 156 clinical trials in which an experimental drug or treatment protocol was compared to a placebo group and an untreated group, and specifically asked whether the placebo group improved compared to the untreated group. Hróbjartsson and Götzsche found that in studies with a binary outcome (patients were classified as improved or not improved) the placebo group had no statistically significant improvement over the no-treatment group. Similarly, there was no significant placebo effect in studies in which objective outcomes (such as blood pressure) were measured by an independent observer. The placebo effect could only be documented in studies in which the outcomes (improvement or failure to improve) were reported by the subjects themselves. The authors concluded that the placebo effect does not have "powerful clinical effects," (objective effects) and that patient-reported improvements (subjective effects) in pain were small and could not be clearly distinguished from bias.

These results suggest that the placebo effect is largely subjective. This would help explain why the placebo effect is easiest to demonstrate 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 the experience of pain, which is often a significant part of many mild and serious illnesses.

How the placebo effect works

There are two main hypotheses for how the placebo effect works, the subject-expectancy effect and conditioning.

Expectancy Effect

The subject-expectancy effect attributes the placebo effect to conscious or unconscious manipulation by patients in reporting improvement. Hróbjartsson and Götzsche argued in their article, "Most patients are polite and prone to please the investigators by reporting improvement, even when no improvement was felt." Subjective bias can also be unconscious, where the patient believes she is improving as a result of the attention and care she has received.

Conditioning

Classical conditioning is a type of associative learning where the subject learns to associate a particular stimulus with a particular response. It is difficult to tell the difference between conditioning and the expectancy effect when the outcome is subjective and reported by the patient. However, conditioning can result in measurable biological changes similar to the changes seen with the real treatment or drug. For example, studies showing that placebo treatments result in changes in brain function similar to the real drug are probably examples of conditioning resulting in objectively measurable results. (Sauro 2005, Wager 2004, Leuchter 2002)

The use of placebos in medical practice

The ethics of prescribing placebos in medical practice is highly debated. Some practitioners argue that the use of placebos is sometimes justified because it will do no harm and may do some good. With the publication of studies by Hróbjartsson and Götzsche and others, the proposition that placebos may do some good is under fire.

A study of Danish general practitioners found that 48% had prescribed a placebo at least 10 times in the past year. The most frequently prescribed placebos were antibiotics for viral infections, and vitamins for fatigue. Specialists and hospital-based physicians reported much lower rates of placebo use. (Hrobjartsson 2003) A 2004 study in the British Medical Journal of physicians in Israel found that 60% used placebos in their medical practice, most commonly to "fend off" requests for unjustified medications or to calm a patient. Of the physicians who reported using placebos, only 15% told their patients they were receiving placebos or non-specific medications. (Nitzan 2004) An accompanying editorial stated,

"The placebo effect, thought of as the result of the inert pill, can be better understood as an effect of the relationship between doctor and patient. Adding the doctor's caring to medical care affects the patient's experience of treatment, reduces pain, and may affect outcome. This survey makes it clear that doctors continue to use placebos, and most think they help."

The editorial suggested there were problems with Hróbjartsson and Götzsche's methods and argued that their results show that placebos can't cure everything, but don't prove that the placebo effect cures nothing. The editorial concluded, "We cannot afford to dispense with any treatment that works, even if we are not certain how it does." (Spiegel 2004)

The editorial prompted responses on both sides of the issue.BMJ posted a series of responses to Dr. Siegel's editorial online in their rapid response section. Selected responses were published in later issues of the Journal.

Critics of the practice responded that it is unethical to prescribe treatments that don't work, and that telling a patient that a placebo is a real medication is deceptive and harms the doctor-patient relationship in the long run. Critics also argued that using placebos can delay the proper diagnosis and treatment of serious medical conditions.
Defenders of the use of placebos suggested that placebos do not work in clinical trials because the subjects know they might be getting a placebo, but do work in medical practice where the patient believes she is getting an active drug. Other writers pointed to the empirical data showing that placebos can have measurable biological effects, especially in pain relief (see above), or argued that the use of a placebo to "please the patient" fosters real healing as part of a caring doctor-patient relationship. (Barfod 2005, Di Blasi 2005)

About 25% of physicians in both the Danish and Israeli studies used placebos as a diagnostic tool to determine if a patient's symptoms were real, or if the patient was malingering. Both the critics and defenders of the medical use of placebos agreed that this was unethical. The BMJ editorial said, "That a patient gets pain relief from a placebo does not imply that the pain is not real or organic in origin...the use of the placebo for 'diagnosis' of whether or not pain is real is misguided."

The placebo effect is an active area of research and discussion and it is possible that a clear consensus regarding the use of placebos in medical practice will emerge in the future.

There is general agreement that placebo control groups are an important tool for controlling for several types of possible bias, including the placebo effect, in double blind clinical trials.

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.

Notes

References

Barfod TS. 2005. Placebos in medicine: placebo use is well known, placebo effect is not. BMJ. 330:45. PMID 15626817.
Beecher, H. K. 1955. The powerful placebo. Journal of the American Medical Association, 159:1602-1606. PMID 13271123. (Original article describing a widespread placebo effect)
Benedetti F, Pollo A et al. Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses. J Neurosci. 23:4315-4323. PMID 12764120
Di Blasi Z, Reilly D. 2005. Placebos in medicine: medical paradoxes need disentangling. BMJ. 330:45. PMID 15626818.
Evans D. 2005. Suppression of the acute-phase response as a biological mechanism for the placebo effect. Med Hypotheses. 64:1-7. PMID 15533601.
Hrobjartsson A, Norup M. 2003. The use of placebo interventions in medical practice--a national questionnaire survey of Danish clinicians. Eval Health Prof. 26:153-165. PMID 12789709.
Hrobjartsson A, Gotzsche P. 2001. Is the Placebo Powerless? An Analysis of Clinical Trials Comparing Placebo with No Treatment. N Engl J Med. 344:1594-602. PMID 11372012.
Hrobjartsson A, Gotzsche P. 2004. Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment. J Intern Med. 256:91-100. PMID 15257721
Khan A, Warner HA, and Brown WA. 2000. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: an analysis of the Food and Drug Administration database. Arch Gen Psychiatry 57:311-317. PMID 10768687
Leuchter AF, Cook IA et al. Changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry. 159:122-129. PMID 11772700.
New Scientist Space. March 19, 2005. 13 Things that do not make sense. URL accessed May 8, 2006.
Nitzan U, Lichtenberg P. 2004. Questionnaire survey on use of placebo. BMJ 329:944-946. PMID 15377572.
Sauro MD. 2005. Endogenous opiates and the placebo effect: a meta-analytic review. J Psychosom Res. 53:115-120. PMID 15820838.
Spiegel D. 2004. Placebos in practice. BMJ. 329:927-928. PMID 15499085.
Wager TD, Rilling JK, Smith EE et al. 2004. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science. 303:1162-1167. PMID 14976306

Additional references

An overview of the placebo effect and how it influences the study of alternative medicines.
Evans D. 2004. Placebo: Mind over Matter in Modern Medicine. HarperCollins (UK) / Oxford University Press (US). ISBN 0195220544.
Evans M. 2000. Justified deception? The single blind placebo in drug research. J Med Ethics. 26:188-193. PMID 10860211.
Harrington, Anne, ed. 1997. The Placebo Effect: An Interdisciplinary Exploration. Cambridge: Harvard University Press. ISBN 067466984-X
Kienle GS, Kiene H. 1997. The powerful placebo effect: fact or fiction? J Clin Epidemiol. 50:1311-8. PMID 9449934. Challenges Beecher's original article.
McDonald CJ, McCabe GP. 1989. How much of the placebo 'effect' is really statistical regression? Stat Med. 2:417-27. PMID 2814076.
Senn SJ. 1988. How much of the placebo 'effect' is really statistical regression? ^* Stat Med. 7:1203. PMID 3201046.
Senn SJ. 1992. The ignoble lie comment. J Clin Epidemiol. 45:1338-40.
Senn SJ. 1996. A personal view of some controversies in allocating treatment to patients in clinical trials. Stat Med. 14:2661-74. PMID 8614742.
Senn SJ. 1997. Are placebo run ins justified? ^* BMJ 314:1191-3. PMID 9146400.
Senn SJ. 2001. The Misunderstood Placebo. Applied Clinical Trials 10:40-46.
Senn SJ. 2002. Ethical considerations concerning treatment allocation in drug development trials. Statistical Methods in Medical Research volume 11, pp.403-411.
Senn SJ. 2003. Dicing with Death: Chance, Risk and Health (Cambridge University Press: Cambridge, UK. ISBN 0521540232.
Zubieta JK, Bueller JA et al. 2005. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci. 25:7754-7762. PMID 16120776.

External links

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

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