Placebo

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A placebo is a substance or procedure a patient accepts as medicine or therapy, but which has no verifiable therapeutic activity. The placebo effect (or placebo response) is a therapeutic effect following administration of a placebo,^[1] or more generally: is the psychosocial effect of medical treatment.^[2] Effective on 30% of humans and only for some conditions, it is also known as the non-specific effect or subject-expectancy effect. A 2008 study showed the placebo response may be genetically determined.^[3] In a placebo controlled trial some participants take a placebo as a control while others take the therapy being investigated. Most well-designed studies include a placebo where practical and ethical.

Contents 1 Placebos 1.1 Etymology 1.2 Inertness 1.3 Doctor-patient relationship 1.4 Use as morale-boosters 1.5 "Placebo" as a pejorative 2 Placebo effect 2.1 Origin of the term "placebo effect" 2.2 Nocebo 2.3 Concept 2.4 Modern clinical application 2.5 Isolation of cause 2.6 Effect on various symptoms 2.7 Objective and subjective effects 2.8 Mechanism for the effect 2.9 Biological substrates of the placebo response 3 Placebo-controlled studies 4 See also 5 External links 6 References 6.1 Books 6.2 History of medicine 6.3 Modern research 6.4 General audience

[edit] Placebos

[edit] Etymology

The word placebo is Latin for I will please. It is in Latin text in the Bible (Psalm 114:1–9, Vulgate version), and was known via the Office of the Dead church service. From that, a singer of placebo became associated with someone who falsely claimed a connection to the deceased to get a share of the funeral meal, and hence a flatterer.

The word obecalp, "placebo" spelled backwards was coined by an Australian doctor in 1998 when he recognised the need for a freely available placebo.^[4] The word is sometimes used to make the use or prescription of fake medicine less obvious to the patient.^[5]

[edit] Inertness

When a placebo is administered to mimic a previously administered drug, it may also incur the same side effects as the authentic drug (see Pavlov). Most of these effects are thought to be a psychological triggering of a physical response. Not all forms of placebo administration are equally effective, and some disease states are entirely resistant to the placebo effect. A placebo that involves ingestion, injection, or incision is often more powerful than a non-invasive technique. Placebos administered by authority figures such as shamans, general practitioners and other trusted figures may also be more powerful than when the psychological or spiritual authority figure is absent.

[edit] Doctor-patient relationship

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. (Hróbjartsson & Norup 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. An accompanying editorial suggested the study by Hróbjartsson and Gøtzsche^[6][7] (see below under Objective and subjective effects) was flawed 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.

• 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)

BMJ posted a series of responses to Spiegel's editorial online in their rapid response section. Selected responses were published in later issues of the Journal.

In addition, there are the impracticalities of placebos:

• Roughly only 30% of the population seems susceptible to placebo effects, and it is not possible to determine ahead of time whether a placebo will work or not.
• All placebo effects eventually wear off, thus making the placebo effect impractical for long term or chronic medical matters.
• Patients rightfully want immediate relief or improvement from their illness or symptoms. A non-placebo can often provide that, while a placebo might not.
• Legitimate doctors and pharmacists could open themselves up to charges of fraud since sugar pills would cost pennies or cents for a bottle, but the price for a "real" medication would have to be charged to avoid making the patient suspicious.
• Unscrupulous medical practitioners could swindle patients with fake surgeries and sugar pills, then later claim that they only meant to help their patients by using "placebos".

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 British Medical Journal 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 those not in delirium are told they are being given a powerful dose of painkiller.

There is general agreement that placebo control groups are an important tool for controlling 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.

[edit] Use as morale-boosters

Hooper’s (1811) Quincy’s Lexicon-Medicum defines placebo as "an epithet given to any medicine adapted more to please than benefit the patient".

In the practice of medicine it had been long understood that, as Ambroise Paré (1510–1590) had expressed it, the physician’s duty was to "cure occasionally, relieve often, console always" ("Guérir quelquefois, soulager souvent, consoler toujours").

According to Jewson, eighteenth century English medicine was gradually moving away from the patient having a considerable interaction with the physician—and, through this consultative relationship, having an equal influence on the construction of the physician’s therapeutic approach—and it was gradually moving towards that of the patient being the recipient of a far more standard form of intervention that was determined by the prevailing opinions of the medical profession of the day. (Jewson 1974; Jewson 1976)

Jewson characterizes this as parallel to the changes that were taking place in the manner in which medical knowledge was being produced; namely, a transition all the way from "bedside medicine", through "hospital medicine", to "laboratory medicine" (Jewson 1976, p.227)(for more on the effect of the development of various types of medical technology see Medical sign#Increased reliance on signs).

From this point of view, the last vestiges of the "consoling" approach to treatment are to be found in the administration – often without any sort of adequate history being taken or any sort of appropriate physical examination being made (Carter 1953, p.823) – of the morale-boosting and pleasing remedies, such as the "sugar pill", electuary or pharmaceutical syrup; all of which had no known pharmacodynamic action.

Those doctors who provided their patients with these sorts of morale-boosting therapies (which, whilst having no pharmacologically active ingredients, provided reassurance and comfort) did so either to reassure their patients whilst the Vis medicatrix naturae (i.e., "the healing power of nature") performed its normalizing task of restoring them to health, or to gratify their patients’ need for an active treatment.

Some statements about placebos in scientific articles are:

• Cooper (1823, p.259): "[When applying] the compound decoction of the sarsaparilla … [in cases of] irritable ulcer, … some think it placebo; others have a very high opinion of its efficacy … [when it is used] after the use of mercury, it diminishes the irritability of the constitution, and soon soothes the system into peace".
• Shapiro (1968, p.656): "[This use of the term "placebo" is a form of] positioning … Introduction of the word placebo to describe a class of treatments not previously specified was an important development in the history of methodology and medicine."
• Handfield-Jones (1953): "some patients are so unintelligent, neurotic, or inadequate as to be incurable, and life is made easier for them by placebo".
• Platt (1947, p.307): "the frequency with which placebos are used varies inversely with the combined intellligence of the doctor and his patient".
• Steele (1891, pp 277–278)"To argue with a man, and especially with a woman, that there is little the matter with them might be thought injudicious, and to advise them to return at a more convenient occasion requires more time and resolution than writing out a prescription or administering a placebo."
• But Shapiro (1968, p.679): "If a placebo is prescribed by a physician because it is thought that it will help the patient, then it is a specific [remedy] and therefore not a placebo [at all]."
• An editorial in the British Medical Journal of 19 January 1952 (p.150): "But it is a fallacy to suppose that an inactive medicine can do no harm. If prescribed in a perfunctory way for a patient needing explanation and reassurance it may increase faith in his disease rather than in the remedy, and a doctor who gives a placebo in the wrong spirit may harm the patient."
• Pepper (1945, p.411): "There may be a time when during the carrying out of diagnostic tests it is undesirable to give potent medicine lest it interfere with the tests and yet the patient must be encouraged by treatment. … there is a certain amount of skill in the choice and administration of a placebo. In the first place, it must be nothing more than what the name implies a medicine without any pharmacologic action whatever. Even a mild sedative is not a true placebo. Secondly, its name must be unknown to even the most inveterate patient who knows most drugs by name and is always quick to read the prescription. If the medicines named are familiar, the type of patient who needs a placebo will promptly exclaim that this or that drug had been tried and "had not helped me" or "had upset my stomach". It is well if the drug have a Latin and polysyllabic name; it is wise if it be prescribed with some assurance and emphasis for psychotherapeutic effect. The older physicians each had his favorite placeboic prescriptions—one chose Tincture of Condurango, another the Fluidextract [sic] of Cimicifuga nigra. Certainly this latter by its Latin name might be expected to have more supratentorial action than if one merely wrote for the Black Cohosh, and Condurango would be more effectual than sugar of milk." Pepper's assertion that a placebo "must be nothing more than what the name implies"—namely that it must be "a medicine without any pharmacologic action whatever"—in order for it to be called a placebo, is most significant.
• Findley (1953), p.1826 & p.1824: "[If the placebo is not] used as an instrument of deception, but as a technique for cementing the emotional bond which must attach doctor to patient if any form of treatment is to be really successful… [it was] the most important weapon the physician has … [specifically because] in proportion as this [doctor-patient] bond is firm, the [patient's] need for drugs will likely diminish."
• Leslie (1954, p.854): "Because medicine has been so concerned with its scientific growth, too little attention has been paid to advancing the art of medicine, to which therapy with placebos belongs, and consequently knowledge of the use of placebos has not progressed significantly."
• Carruthers, Hoffman, Melmon & Nierenberg (2000, p.1268): "In clinical practice, where a majority of patient visits are for conditions that cannot be explained on a pathophysiologic basis of for which no specific treatment is available, it is essential that physicians understand the concepts and principles of placebos and placebo effects and, when appropriate, use them correctly".

[edit] "Placebo" as a pejorative

Useless decoctions, drugs, treatments, remedies, and procedures are given the pejorative label placebo.

In the 14th century the English word "placebo" denoted a sycophant and a useless flatterer, but this usage became obsolete.

The second edition of Motherby’s (1785) New Medical Dictionary defines "placebo" as "a common place method or medicine" (not "a common place method of medicine" as often misquoted.)

Because this usage does not appear in English (or in any English, French, German, Italian, or Portuguese dictionary) before Motherby’s 1785 edition, Shapiro (1968, pp.656–657) is certain that this pejorative use of placebo was coined by Motherby. That Samuel Johnson's 1755 Dictionary of the English Language has no entry for placebo (or for placebo-singer or singer of placebo, (see Placebo at funeral), strongly supports Shapiro's contention.

[edit] Placebo effect

[edit] Origin of the term "placebo effect"

Graves was possibly the first to mention the "placebo effect", when he spoke in 1920 of "the placebo effects of drugs" being manifested in those cases where "a real psychotherapeutic effect appears to have been produced". (Graves 1920, p.1135)

In the 1930s Evans and Hoyle (1933), (using 90 subjects), and Gold, Kwit and Otto (1937), (using 700 subjects), published studies which compared the outcomes from the administration of an active drug and a dummy simulator (which both research groups called a "placebo") in the same trial. Neither experiment displayed any significant difference between drug treatment and placebo treatment;^{[citation needed]} leading the researchers to conclude that the drug exerted no specific effects in relation to the conditions being treated.

In 1946, the Yale biostatistician and physiologist E. Morton Jellinek was the first to mention either a "placebo reaction" or a "placebo response". He spoke of a "response to placebo" (p.88), those who "responded to placebo" (p.88), a "reaction to placebo" (p.89), and of "reactors to placebo" (p.90). This suggests that to Jellinek the terms "placebo response" and "placebo reaction"—or the terms "placebo responder" and "placebo reactor"—were identical and interchangeable.

General literature attributes the term "placebo effect" to Henry K. Beecher's 1955 paper The Powerful Placebo, where, however, he only speaks of placebo effects when he is contrasting them with drug effects. Otherwise, he always speaks of "placebo reactors" and "placebo non-reactors". Beecher (1952), Beecher et al. (1953), Beecher (1959), consistently speak of "placebo reactors" and "placebo non-reactors"; they never speak of any "placebo effect". Beecher (1970) simply speaks of "placebos".

[edit] Nocebo

Main article: Nocebo

In the opposite effect, a patient who disbelieves in a treatment may experience a worsening of symptoms. This effect, now called by analogy the "nocebo effect" (Latin nocebo = "I will 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, but due to other factors, such as the patient's mentality towards his or her ability to get well, or even purely coincidental worsening of symptoms.^[8]

[edit] Concept

Reports in Proceedings of the National Academy of Sciences show placebos can reduce pain in humans. Researchers at Columbia and Michigan University have shown that the brains of volunteers who believed that what they were taking was pain medication released opioids, or natural pain relief. (Donaldson James 2007) According to that ABC report the Food and Drug Administration contends that as many as 75 percent of patients have had responses to sugar pills. It pointed out that all major clinical trials use placebo groups because the effect is significant and to be expected.

This effect has been known since the early 20th century. Generally, one third of a control group taking a placebo shows improvement, and Harvard’s Herbert Benson says that the placebo effect yields beneficial clinical results in 60–90% of diseases, including angina pectoris, bronchial asthma, herpes simplex, and duodenal ulcers. (Benson & Friedman 1996)

Several common ideas about placebos, however, are based on misconceptions and misreading of the research literature:

• Since Beecher's 1955 study appeared (Beecher 1955), it has been claimed that about one third of the therapeutic effect observed in a typical trial is attributable to the placebo effect, but this is a misinterpretation of Beecher's results. In the "meta-analytic" section of his paper he gave the proportion of subjects across 15 trials deemed to have "been satisfactorily relieved by placebo" as 35.2% +/- 2.2%. This, if anything, is an estimate of the frequency of 'placebo-responders' in the aggregate trial group, but says nothing about the magnitude of the effect.
• Beecher, intentionally or otherwise, gave currency to the idea that the placebo effects were roughly constant at around 35%, and that the term could be usefully applied to all those variables otherwise called "non-specific" contributors to therapeutic outcomes – the natural (and unknowable) course of diseases, regression to the mean, expectation effects, changes in effect and other unquantifiable psycho-somatic features of illness, beliefs and therapeutic communication, etc. If anything is clear from subsequent studies, it is that the placebo effect is not constant, but strikingly variable. Placebo response rates all the way from zero to 100% have been reported in virtually every clinical condition studied (the variation in Beecher's own series was 15–58%). The so-called effect appears to be both universal and utterly unpredictable.
• Beecher, who was concerned to promote the use of Randomised controlled trials (RCTs) in clinical research, made an unjustified assumption which is almost certainly false - that placebo effects in the intervention and control arms of a trial will be identical, or nearly so, and independent of the therapeutic effects. In the rationalization of RCTs which followed, this claim has never been rigorously defended, and in specific instances, can be easily refuted.^[9]
• The original 1955 article of Beecher "The Powerful Placebo" claimed a 35% placebo effect in 15 studies. The original article was in 1997 re-analysed and "no evidence was found of any placebo effect in any of the studies" used by Beecher. (Kienle & Kiene 1997) The claimed "effects" were produced by spontaneous improvement, fluctuation of symptoms, regression to the mean, additional treatment, conditional switching of placebo treatment, scaling bias, irrelevant response variables, answers of politeness, experimental subordination, conditioned answers, neurotic or psychotic misjudgment, psychosomatic phenomena, misquotation, etc.
• Kaptchuk (1998a; 1998b) has shown that both the name and the concept of placebo were transferred from at least 200 years of use in clinical practice, in the decade following the second world war, to a new role required by the methodology of what was then the new discipline of 'clinical research'. Earlier usage corresponded to its Latin etymology – a harmless pill or potion given knowingly to patients who were either hard to please or hard to cure. The first clear example cited in the OED is from 1811. But during the post-war therapeutic revolution, it became the trashcan into which all the confounding factors that disturb therapeutic assessments were tipped. In Beecher's terms, it became a powerful if enigmatic distraction to researchers, whose results would be contaminated without rigorous procedures for its exclusion. Its modern use is therefore quite recent, and closely related to the adoption of the RCT as the methodological gold standard for trials of therapy.
• A considerable body of work has attempted to elucidate the 'mechanism' of the placebo effect – but without much success. Proposals ranging from 'suggestibility' and various other psychological hypotheses, to neuro-endocrine studies, and attribution of the effect to statistical artifacts, have turned out to be flawed in various ways, so that clinical researchers have no more idea of what is really going on in the control arms of their trials than did Hippocrates. It seems unlikely that this deeply unsatisfactory situation will be resolved by a new attempt to answer the old question; instead, as has been suggested by some of the most thoughtful students, we should expect to find that some part of the conceptual landscape in which this problematic entity resides must be reconstructed before it will come into focus. This view commends itself specially to those scholars who bring to the problem a perspective from outside the clinic – from medical anthropology, history of medicine, philosophy, and statistics.^[10]

[edit] Modern clinical application

Experimenters typically use placebos in the context of a clinical trial, in which a "test group" of patients receives the therapy being tested, and a "control group" receives the placebo. It can then be determined if results from the "test" group exceed those due to the placebo effect. If they do, the therapy or pill given to the "test group" is assumed to have had an effect.

[edit] Isolation of cause

According to Kleijnen and his colleagues (Kleijnen et al. 1994, p.1347), healing is an interactive process between three influences:

1. the self-healing properties of the subject.

(Here, they are referring to an inherent self-healing force (such as that which naturally staunches a bleeding cut) similar to that of the élan vital (“life force”) or the vis medicatrix naturae (“healing power of nature”), per medium of which the patient recovers entirely without the physician’s intervention, rather than to some sort of active, intentional, purposeful arousal of a subject’s optimal physiological, psychosomatic and somatopsychic healing resources by the therapist)

1. the non-specific effects induced by the presence of the therapist and the therapeutic setting.

(The term "non-specific effects" has many advantages; e.g., psychopharmacological research that Hankoff (1999) conducted with colleagues in the 1950s, led them to conclude that “it is best to think of a range of nonspecific factors to account for the response to a medication (which can be both positive and negative), rather than speaking of a placebo reaction or a placebo reactor as an explanation” (p.199). Roberts, et al. (2001) describes these non-specific effects as “the nonpharmacologic benfits of the protocol involvement and of participants’ beliefs that they may be taking an active medication” (p.887))

1. the specific effects of the physical or pharmacological therapeutic interventions.

These effects are not isolated mutually exclusive effects and, rather than just adding, they may help or hinder each other to various degrees. (Kleijnen et al. 1994, p.1349) Also, Hyland (2003, p.348) notes that, in cases where “contextual factors contribute to a strong placebo response”, due to “the potentiating or adjunctive effect of the placebo response”, placebos can be used “potentiate the effect of an active treatment” that would have otherwise been far less efficacious.

From this notion that a “drug” has a specific treatment effect (i.e., the effect for which it has been administered), Perlman (2001, p.283) draws attention to three other treatment effects:

1. non-specific effects: these are the side effects (“which are usually considered deleterious”);
2. unintended effects: these are the placebo effects (“which… are still considered to be for the most part uncontrolled and unscientific”); and
3. serendipitous effects: these are the “serendipitous effects of being in therapy, such as [the] organizing effects of the therapeutic structure, inadvertent role modelling, outside knowledge of the therapist, chance remarks or encounters, and the influence of auxiliary personnel”.

In pursuit of establishing causation, the question “Who does what, with which, and to whom?” is central to task of identifying what are:

• specific effects (those for which the treatment was administered),
• non-specific effects (predictable "side effects"),
• unintended effects (i.e., the placebo responses),
• serendipitous effects of treatment (i.e., effects of the subject just being "in therapy"); Perlman (2001, p.283) in discussing this suggests these as examples:
  • the "organizing effects of the therapeutic structure",
  • "inadvertent role modeling",
  • "outside knowledge of the therapist",
  • "chance remarks or encounters",
  • "the influence of auxiliary personnel" ("this category includes doormen, receptionists, cashiers, secretaries, security guards, janitors, and child care attendants", p.287).

Gaddum (1954) also recognizes that "changes in the incidence or severity of diseases in a hospital may be due to changes in the diet or changes in the nurses, which happen to coincide with the introduction of a new treatment" (pp.195–196).

In experiments with the common cold by Gold, Kwit and Otto (Gold et al. 1937), in accounting for why those who received the placebo drug often experienced considerable benefit, Gold and his colleagues supposed that other, non-drug-related factors may have made a significant contribution to the apparent efficacy of the supposedly active drug, such as:

1. Spontaneous variations in the course of the pain.
2. Change in the weather.
3. Change of occupation or amount of work.
4. Change of diet.
5. Change in eating habits with increase in the amount of rest before and after meals.
6. Condition of the bowels.
7. Emotional stress.
8. Change in domestic affairs.
9. Confidence aroused in the treatment.
10. Encouragement afforded by any new procedure.
11. A change of the medical adviser. (Gold et al. 1937, p.2177)

Also, due to the difficulty in ascribing causation, many phenomena overlap with, and are thus misattributed to, subjects' placebo responses (the phenomena are known as "confounders" or "lurking variables", such as:

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

[edit] Effect on various symptoms

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 et al. 2003, Wager et al. 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 – (Latin for "swelling, redness, heat, and pain").
• Sickness behavior: lethargy, apathy, loss of appetite, and increased sensitivity to pain.

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 et al. 2000)

A May 7, 2002 article in The Washington Post titled "Against Depression, a Sugar Pill Is Hard to Beat" stated, "A new analysis has found that in the majority of trials conducted by drug companies in recent decades, sugar pills have done as well as -- or better than -- antidepressants. Companies have had to conduct numerous trials to get two that show a positive result, which is the Food and Drug Administration's minimum for approval. What's more, the sugar pills, or placebos, cause profound changes in the same areas of the brain affected by the medicines, according to research published last week... the makers of Prozac had to run five trials to obtain two that were positive, and the makers of Paxil and Zoloft had to run even more... When Leuchter compared the brain changes in patients on placebos, he was amazed to find that many of them had changes in the same parts of the brain that are thought to control important facets of mood... Once the trial was over and the patients who had been given placebos were told as much, they quickly deteriorated. People's belief in the power of antidepressants may explain why they do well on placebos..." ^[11] A meta-analysis in the Journal of Psychiatric Research evaluated the effect of placebos for 12 weeks after an initial 6-8 weeks of successful therapy. They found that 79% of depressed patients receiving placebo remained well compared to 93% of those receiving antidepressants.^[12]

Withdrawal symptoms on discontinuation

The Women's Health Initiative study of hormone replacement therapy for menopause was discontinued after participants still in the program had been taking either hormones or placebo for an average of 5.7 years. Moderate or severe withdrawal symptoms were reported by 40.5% of those on placebo compared to 63.3% of those on hormone replacement. Pain and stiffness (musculoskeletal symptoms) were the most frequently reported symptoms in both the placebo group (22.2%) and the hormone group (36.8%), exceeding other symptoms by more than 10%. Of those reporting pain and stiffness, 54.7% in the hormone group and 38.3% in the placebo group had these symptoms at the onset of therapy. Tiredness was the second most frequently reported withdrawal symptom (21.3% hormone, 11.6% placebo) and hot flashes/night sweats the third (21.2% hormone, 4.8% placebo). (Ockene et al. 2005) Only the vasomotor symptoms (hot flashes/night sweats) were acknowledged to be verified effects of menopause by a 2005 National Institutes of Health panel. (NIH State-of-the-Science Panel 2005)

These results may indicate some learned response concerning which withdrawal symptoms appear in a placebo group as well as in the subjects who received therapy, with a greater effect on pain and tiredness than on vasomotor symptoms.

[edit] Objective and subjective effects

Hróbjartsson and Peter Gøtzsche published a study in 2001^[6] and a follow-up study in 2004 ^[7] questioning the nature of the placebo effect. They performed two meta-analyses involving all published 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 Gøtzsche 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 reporting bias.

[edit] Mechanism for the effect

It is universally accepted that, for a placebo response to occur, the subject must believe an effective medication (or other treatment) has been administered to them. This is quite different from the case of an "active drug", where the drug response is generated even in the case of covert administration, in other words regardless of whether the patient knows or doesn't know they have received any medication.

The question of just how and why placebo responses are generated is not an abstract theoretical issue; it has wide implications for both clinical practice and the experimental evaluation of therapeutic interventions.

In recent times, several hypotheses have been offered to account for these placebo responses which, whilst emphasizing different factors, are not mutually exclusive.

Expectancy effect

The subject-expectancy effect attributes the placebo effect to conscious or unconscious manipulation by patients in reporting improvement. Hróbjartsson and Gøtzsche argued in their article, "Most patients are polite and prone to please the investigators by reporting improvement, even when no improvement was felt."^[7] 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 et al. 2004)

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).

Health management system

An evolutionary medicine explanation is the health management system. According to evolutionary medicine, most symptoms such as fever, pain, and sickness behavior are evolved responses. Fever, for example, is an evolved self-treatment that clears bacteria or viruses through raised body temperature. These evolved responses are created by the brain through its top down control upon the body. Such evolved responses are, therefore, not necessary, and often do not occur when they have a cost that outweighs their benefit (such as the lack of fever in response to infection during malnutrition or late pregnancy). To reduce unnecessary use, a health management system evolved in the brain to ensure that evolved responses are deployed only when they are advantageous. The likelihood that the body will get well without them (such as when taking medications) is one factor in humans that will determine their most advantageous use. The placebo effect arises when false information about medications misleads the health management system about the likelihood of getting well so that it weighs against deploying a self-treatment.^[13]

Role of endogenous opiates

The discovery in 1975 of Endogenous opiates alias endorphins (substances like opiates but naturally produced in the body) have changed matters in investing placebo effect. 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 psychological reaction causing release of natural opiates. (Sauro 2005)

[edit] Biological substrates of the placebo response

A placebo response can amplify, diminish, nullify, reverse, or even divert the action of an active drug, and the study of placebo responses is essentially the study of the psychosocial construct surrounding a patient. (Koshi & Short 2007) Because a placebo response is just as significant in the case of an active drug as it is in the case of an inert dummy drug, the more that we can discover about the mechanisms that produce placebo responses, the more we can enhance their effectiveness and convert their potential efficacy into actual relief, healing and cure.

Recent research^[14] strongly indicates that a placebo response is a complex psychobiological phenomenon, contingent upon the psychosocial context of the subject, that may be due to a wide range of neurobiological mechanisms, with the specific response mechanism differing from circumstance to circumstance. The very existence of these "placebo responses" strongly suggest that "we must broaden our conception of the limits of endogenous human control" (Benedetti et al. 2005, p.10390); and, in recent times, researchers in a number of different areas have demonstrated the presence of biological substrates, unique brain processes, and neurological correlates for the "placebo response":

• 2001: de la Fuente-Fernández and colleagues reported their PET scan findings on test subjects with Parkinson's disease.
• 2002: Petrovic and colleagues reported their PET scan findings on test subjects in a trial of opioid analgesia.
• 2002: Mayberg and colleagues reported their PET scan findings on test subjects with unipolar depression.
• 2004: Wager and colleagues reported their fMRI scan findings on test subjects in a trial of placebo analgesia.
• 2004: Lieberman and colleagues reported their PET scan findings on test subjects with Irritable bowel syndrome.
• 2006: Bingel and colleagues reported their fMRI scan findings on test subjects in a trial of placebo analgesia.
• 2006: Zubieta and colleagues reported their PET scan findings on test subjects in a trial of placebo analgesia.
• 2006: Sarinopoulos and colleagues reported their fMRI scan findings on test subjects in a trial neural responses to a highly aversive bitter taste.

A complex fMRI-centred study by McClure et al. (2004) on the brain responses of subjects who had previously expressed a preference for one or other of the similar soft drinks Pepsi and Coca-Cola, demonstrated that "brand information", which "significantly influences subjects’ expressed preferences", is processed in an entirely different brain area from the area activated in blind taste tests (when their "preferences are determined solely from sensory information").(McClure et al. 2004, p.385) This supports the claim that there are unconscious brain processes that activate the "placebo response".

[edit] Placebo-controlled studies

Main article: Placebo-controlled studies

While the placebo effect advantages medical treatment by providing an additional therapeutic effect, it causes a problem in evaluating new clinical treatments. This is because the apparent benefits of a new treatment (usually a drug but not necessarily so) might not derive from that treatment but the placebo effect. This is particularly likely given that new therapies seem to have greater placebo effects. As a result, clinical trials control for this by including a group of subjects that receives sham treatment. The subjects in such trials are blinded as to whether they receive the treatment or a placebo. Often clinical trials are double blinded so that the researchers also do not know which subjects are receiving the active or placebo treatment.

The placebo effect in such clinical trials is weaker than in normal therapy since the subjects are not sure whether the treatment they are receiving is active.^[15]

To knowingly give a person a placebo when there is an effective treatment is a bioethically complex issue. This is because while doing this might provide information about the effectiveness of a treatment, it violates the rights of that person to receive the best available treatment. This issue is covered by the Declaration of Helsinki.

[edit] See also

Look up placebo in Wiktionary, the free dictionary.

[edit] External links

• The Placebo Effect at the Skeptic's Dictionary
• The Placebo Effect explained on YouTube
• Interview on Placebos Richard Dawkins and Nicholas Humphrey

[edit] References

[edit] Books

[edit] History of medicine

[edit] Modern research

[edit] General audience