Drugs & Medication

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 (Latin nocebo, "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.

Contents 1 Placebo-controlled studies 1.1 Notable placebo effect absences 1.2 Placebo and pain 1.3 Placebo and depression 1.4 Endogenous Opiates 2 Objective or subjective effects? 3 How the placebo effect works 3.1 Expectancy Effect 3.2 Conditioning 3.3 Motivation 4 The use of placebos in medical practice 5 Methodology of Administration 6 Confounders mistaken for placebo effect 7 Notes 8 References 9 Additional references 10 External links

Placebo-controlled studies

Beecher (1955) reported that about a quarter of patients who were administered a placebo, for example 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, due to the difficulty involved). 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?

Hrobjartsson and Götzsche published a study in 2001 and a follow-up 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. Hrobjartsson and Götzsche found that in studies with a binary outcome, meaning 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, stomachache, 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 three main hypotheses for how the placebo effect works, the subject-expectancy effect, conditioning and motivation.

Expectancy Effect

The subject-expectancy effect attributes the placebo effect to conscious or unconscious manipulation by patients in reporting improvement. Hrobjartsson 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 he is improving as a result of the attention and care he has received.

Conditioning

Classical conditioning is a type of associative learning where the subject learns to associate a particular stimulus with a particular response. In this case the stimulant is the substance perceived as medicine but is the placebo, and the response is the relief of symptoms. 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)

Motivation

Motivational explanations of the placebo effect have typically considered the placebo effect to be an outcome of one’s desire to feel better, reduce anxiety, or cooperate with an experimenter or health care professional (Price et al. 1999, Margo 1999). The motivational perspective is supported by recent research showing that nonconscious goals for cooperation can be satisfied by confirming expectations about a treatment (Geers et al. 2005).

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.

In research experimental studies, the method of establishing a proper control group to eliminate the placebo effect has also been difficult, particularly for surgical and therapy interventions that are not pharmaceutical in nature. Notably, there has been much debate of whether to use a placebo pill or conduct a sham procedure as a control.

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.^[1]

• 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 he or 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 administration may prove to be a useful treatment in some specific cases where recommended drugs can not be used. For example, burn patients who are experiencing respiratory problems cannot often be prescribed opioid (morphine) or opioid derivatives (pethidine), as these can cause further respiratory depression. In such cases placebo injections (normal saline, etc.) are of use in providing real pain relief to burn patients if they (those not in delirium) are told that are being given a powerful dose of painkiller.

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.

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.

Methodology of Administration

Placebos are things like sugar pills, that look like real treatments but in fact have no physical effect. They are used to create "blind" trials in which the participants do not know whether they are getting the active treatment or not, so that physical effects can be measured independently of the participants' expectations. There are various effects of expectations, and blind trials control all of these together by making whatever expectations there are equal for all cases. Placebos aren't the only possible technique for creating blindness (unawareness of the intervention): to test the effectiveness of prayer by others, you just don't tell the participants who has and has not had prayers said for them. To test the effect of changing the frequency of fluorescent lights on headaches, you just change the light fittings at night in the absence of the office workers (this is a real case).

Related to this is the widespread opinion that placebo effects exist, where belief in the presence of a promising treatment (even though it is in fact an inert placebo) creates a real result e.g. recovery from disease. Placebos as a technique for blinding will remain important even if there is no placebo effect, but obviously it is in itself interesting to discover whether placebo effects exist, how common they are, and how large they are. After all, if they cure people then we probably want to employ them for that.

Claims that placebo effects are large and widespread go back to at least Beecher (1955). However Kienle and Kiene (1997) did a reanalysis of his reported work, and concluded his claims had no basis in his evidence; and then Hrobjartsson & Gotzsche (2001) did a meta-analysis or review of the evidence, and concluded that most of these claims have no basis in the clinical trials published to date. The chief points of their skeptical argument are:

• Only trials that compare a group that gets no treatment with another group that gets a placebo can test the effect.
• Most claims are based on looking at the size of the improvement measured in placebo groups in trials comparing only placebo and experimental (active) treatments. This is misleading since (for instance) most diseases have a substantial clearup rate with no treatment: seeing improvements doesn't mean the placebo had an effect. (Put more technically, comparing with the baseline (pretest measure) is vulnerable to regression to the mean.)

Nevertheless, even they conclude that there is a real placebo effect for pain (not surprising since this is partly understood theoretically: Wall, 1999)); and for some other continuously-valued subjectively-assessed effects. A recent experimental demonstration was reported: Zubieta et al. (2005) "Endogenous Opiates and the Placebo Effect" The journal of neuroscience vol.25 no.34 p.7754-7762

This seems to show that the psychological cause (belief that the placebo treatment might be effective in reducing pain) causes opioid release in the brain, which then presumably operates in an analogous way to externally administered morphine.

A recent and more extensive review of the overall dispute is: M. Nimmo (2005) Placebo: Real, Imagined or Expected? A Critical Experimental Exploration Final year undergraduate Critical Review, Dept. of Psychology, University of Glasgow. PDF copy.

Summary

• Placebos are used to create blind trials. They are not the only technique for this, but are a very common and important one.
• Whether or not there is a placebo effect, placebos will remain an important technique for this.
• Recent skeptical meta-analysis of placebo effects suggest that the effect does exist, but only in very limited contexts. The widespread claims are mainly misplaced, based on faulty inferences.
• Placebos are often seen as posing ethical difficulties. Essentially the issues are of two kinds, neither about placebos alone.
  • Deceiving experimental participants, or at least withholding information. This is potentially in tension with the principle of informed consent. This is most acute for experiments that wish not just to achieve blinding, but to measure the effect of expectancies, and so wish to induce expectancies by misinforming (some) participants.
  • Withholding treatment from patients (or education from students). The tension here is between the greater certainty a controlled experiment will give, versus the prior guesses of people and experts. After all, you probably wouldn't do an experiment unless you had some reason to hope a treatment worked; but if you do have such grounds, then your opinion of the best treatment should be given to all patients rather than give some a placebo.

Ways of classifying and comparing such effects Can we organize these (and other) various reported effects in some useful way? What are the effects that might be related?

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.
• Regression to the mean. Cyclical presentation of the disease.
• Errant diagnosis or prognosis.
• Temporary improvement confused with cure.

Notes

1. ^ 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.

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.
• Geers AL et al. 2005. Goal activation, expectations, and the placebo effect. J Pers Soc Psychol. 89:143-159. PMID 16162050.
• 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.
• Margo CE. 1999. The placebo effect. Surv Ophthalmol. 44:31-44. PMID 10466586.
• 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.
• Price DD et al. 1999. An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain. 83:147-156. PMID 10534585.
• 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

• Dodes, John E. "The Mysterious Placebo", Skeptical Inquirer, January/February 1997. Retrieved on 2006-05-08. 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 0-19-522054-4.
• 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 0-674-66984-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.
• Nordenberg, Tamar. "The healing power of placebos", FDA Consumer Magazine, January-February 2000. Retrieved on 2006-05-08.
• Senn SJ. 1988. How much of the placebo 'effect' is really statistical regression? [letter] Stat Med. 7:1203. PMID 3201046.
• Senn SJ. 1992. The ignoble lie [letter; 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? [letter] 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 0-521-54023-2.
• Talbot, Margaret. "The Placebo Prescription", The New York Times Magazine, January 9, 2000. Retrieved on 2006-05-08.
• 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.)