Placebo

Contents 1 Placebos 1.1 Etymology 1.2 Early use 1.3 Inertness 1.4 Doctor-patient relationship 1.5 Use as morale-boosters 1.6 "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 3.1 History of trial design 3.2 Examples of effect 3.3 Methodology of administration 3.4 Use in clinical trials 3.5 Placebo response as an index 3.6 Technical challenges and pitfalls 3.7 Ethical challenges and concerns 4 See also 5 External links 6 References 6.1 Books 6.2 History of medicine 6.3 Modern research 6.4 General audience

A placebo is a substance or procedure a patient accepts as medicine or therapy, but which has no verifiable therapeutic activity. Susceptibility to the placebo effect (roughly 30% in the human population) may be "genetically determined"..

In placebo controlled trials some participants take a placebo while others have the therapy being investigated.

The word placebo has been used with various meanings (see below).

Placebos

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.^[1] The word is sometimes used to make the use or prescription of fake medicine less obvious to the patient.^[2]

Early use

Well-meaning doctors would sometimes give a patient a placebo saying it was a powerful drug. Hooper's 1811 medical dictionary says placebo is "an epithet given to any medicine adapted more to please than benefit the patient."

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.

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^[3][4] (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.

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".

"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.

Placebo effect

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; 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".

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.^[5]

Concept

An example of the placebo effect is the improved performances of runners who were led to believe they were drinking oxygenated water, whereas in reality, the runners were drinking regular tap water. The runners performed better because they thought what they were drinking would enhance their performance.

This is true as well for the "sugar pill." People who believe they are ill may report symptoms of the illness, yet show no observable cause. Doctors have given such patients tablets containing sugar in place of a drug, and found that reported symptoms often decreased, seemingly as a result of the "treatment".

Studies published in Proceedings of the National Academy of Sciences using advances in neuroscience (PET scans) have shown that placebos can noticeably 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 were shown to be spontaneously releasing 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.^[6]
• 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.^[7]

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.

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)

2. 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))

3. 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.

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 behaviour: 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..." ^[8] 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.^[9]

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.

Objective and subjective effects

Hróbjartsson and Peter Gøtzsche published a study in 2001^[3] and a follow-up study in 2004 ^[4] 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.

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, three different hypotheses have been offered to account for these placebo responses — i.e., "expectancy theory" and 'classical conditioning" and motivation — which, whilst emphasizing different factors, are not mutually exclusive and, in fact, overlap to a certain extent.

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."^[4] 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).

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)

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^[10] 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".

Placebo-controlled studies

History of trial design

"Heroic medicine" had begun to fall from favour long before research scientists such as Robert Koch, Louis Pasteur, Frederick Hopkins and Casimir Funk demonstrated that the presence or the absence of specific agents could cause specific diseases, and long before the chemical laboratory orientation of Abraham Flexner’s 1910 Flexner Report had evolved into the evidence-based medicine of the 1970s. As the earliest precursors of modern, scientific, conventional medicine began to emerge, medical scholars began to routinely question:

• the principles of their medical diagnosis and prognosis,
• the efficacy of their conventional medical practices,
• the correctness of their current anatomical, physiological and neurological knowledge, and
• the true scientific status of the drugs and therapies in their pharmacopoeia.

In many cases, active agents were identified in supposedly efficacious treatments; but it was found that some treatments had no efficacy whatsoever; and, regardless of how much they were accepted in the medical profession, or what they were supposed to do, they were medically useless. Many, such as Pepper (1945, p.410) would strongly argue that, before the Countess of Chinchón learned of the medicinal properties of cinchona bark (perhaps the first time a real active ingredient had been isolated and identified), "there was [no] basis for terming anything a placebo".

The aim of a clinical trial is to determine what treatments, delivered in what circumstances, to which patients, in what conditions, are the most efficacious; as well to obtain objective evidence of what treatments are efficacious and also specific (Chambless & Hollon 1998), or are intentionally efficacious and also specific (Lohr et al. 2005).

Gaddum (1954, p.195) wrote: "The first object of a therapeutic trial is to discover whether the patients who receive the treatment under investigation are cured more rapidly, more completely or more frequently, than they would have been without it."

1747 – remedies for scurvy

In 1747, James Lind (1716–1794), the Ship's doctor on HMS Salisbury, conducted what was most likely the first-ever clinical trial when he investigated the efficacy of citrus fruit in cases of scurvy. He randomly divided twelve scurvy patients, whose "cases were as similar as I could have them", into six pairs. Each pair was given a different remedy. Lind’s approach can still be seen in the way that the comparative efficacy of various treatments for particular sorts of cancer are determined, by examining and comparing the five year survival rates of those who have been treated with each of the different interventions. He noted that the pair who had been given the oranges and lemons were so restored to health within six days of treatment that one of them returned to duty, and the other was well enough to attend the rest of the sick. (Dunn 1997, p.F65)

According to Lind’s 1753 Treatise on the Scurvy in Three Parts Containing an Inquiry into the Nature, Causes, and Cure of the Disease, Together with a Critical and Chronological View of what has been Published of the Subject, the remedies were:

1. one quart of cider per day,
2. twenty-five drops of elixir vitriol (sulfuric acid) three times a day,
3. two spoonfuls of vinegar three times a day,
4. a course of sea-water (half a pint every day),
5. two oranges and one lemon each day,
6. an electuary (Dunn 1997, p.F65).

Gaddum (1954, p.196) wrote that the electuary had been recommended to Lind by a hospital surgeon, and that it contained garlic, mustard, balsam of Peru, and myrrh.

1784 – animal magnetism

In 1784, the French Royal Commission looked into the existence of animal magnetism, comparing the effects of allegedly "magnetized" water with that of plain water. (Gauld (1992), p.28) It did not examine the practices of Franz Mesmer, but examined the significantly different practices of his associate Charles d'Eslon (1739–1786).

1799 – Perkins tractors

In 1799, John Haygarth investigated the efficacy of medical instruments called "Perkins tractors", by comparing the results from dummy wooden tractors with a set of allegedly "active" metal tractors. (Green 2002; Haygarth 1801)

1863 – placebo compared with active treatment

In 1863 Austin Flint (1812–1886) conducted the first-ever trial that directly compared the efficacy of a dummy simulator with that of an active treatment; although Flint's examination did not compare the two against each other in the same trial. Even so, this was a significant departure from the (then) customary practice of contrasting the consequences of an active treatment with what Flint described as "the natural history of [an untreated] disease". (Flint 1863, p.18)

Flint’s paper is the first time that either of the terms "placebo" or "placeboic remedy" were ever used to refer to a dummy simulator in a clinical trial.

… to secure the moral effect of a remedy given specially for the disease, the patients were placed on the use of a placebo which consisted, in nearly all of the cases, of the tincture of quassia, very largely diluted. This was given regularly, and became well known in my wards as the placeboic remedy for rheumatism.

Flint (1863, p.21) treated 13 hospital inmates who had rheumatic fever; 11 were "acute", and 2 were "sub-acute". He then compared the results of his dummy "placeboic remedy" with that of the active treatment’s already well-understood results. (Flint had previously tested, and reported on, the active treatment’s efficacy.) There was no significant difference between the results of the active treatment and his "placeboic remedy" in 12 of the cases in terms of disease duration, duration of convalescence, number of joints affected, and emergence of complications (pp.32–34). In the thirteenth case, Flint expressed some doubt as to whether the particular complications that had emerged (namely, pericarditis, endocarditis, and pneumonia) would have been prevented if that subject had been immediately given the "active treatment" (p.36).

1946 – a headache remedy ingredient

In post-World War II 1946, pharmaceutical chemicals were in short supply. One U.S. headache remedy manufacturer sold a drug that was composed of three ingredients: a, b, and c. Chemical b was in short supply.

Jellinek was asked to test whether or not the headache drug's overall efficacy would be reduced if ingredient b was missing.

Jellinek set up a complex trial involving 199 subjects, all of whom suffered from "frequent headaches". (Originally there were 200 subjects, but one did not complete the trial.) The subjects were randomly divided into four test groups. He prepared four test drugs, involving various permutations of the three drug constituents, with a placebo as a scientific control. The structure of this trial is significant because, in those days, the only time placebos were ever used "was to express the efficacy or non-efficacy of a drug in terms of "how much better" the drug was than the "placebo". (Jellinek 1946, p.88) (Note that the trial conducted by Austin Flint is an example of such a drug efficacy vs. placebo efficacy trial.) The four test drugs were identical in shape, size, colour and taste:

• Drug A: contained a, b, and c.
• Drug B: contained a and c.
• Drug C: contained a and b.
• Drug D: a 'simulator', contained "ordinary lactate".

Each time a subject had a headache, they took their group’s designated test drug, and recorded whether their headache had been relieved (or not). Although "some subjects had only three headaches in the course of a two-week period while others had up to ten attacks in the same period", the data showed a "great consistency" across all subjects (Jellinek, 1946, p.88). Every two weeks the groups’ drugs were changed; so that by the end of eight weeks, all groups had tested all the drugs.

The stipulated drug (i.e., A, B, C, or D) was taken as often as necessary over each two-week period, and the two week sequences were:

1. A, B, C, D
2. B, A, D, C
3. C, D, A, B
4. D, C, B, A.

Each group took a test remedy for two weeks. The trial lasted eight weeks, and by the end of the trial all groups had taken each test drug for two weeks (although each group had taken them in a different sequence). Over the entire population of 199 subjects, 120 of the subjects responded to the placebo, and 79 did not; i.e., there were 120 "subjects reacting to placebo" and 79 "subjects not reacting to placebo". (Jellinek 1946, p.89)

At first glance there was no difference between the self-reported "success rates" of Drugs A, B, and C (84%, 80%, and 80% respectively) (the "success rate" of the simulating placebo Drug D was 52%); and, from this, it appeared that ingredient b was completely unnecessary.

However, in quite a remarkable way, the trial eventually did demonstrate that ingredient b did make a significant contribution to the remedy’s efficacy. Examining his data more closely, Jellinek discovered that there was a very significant difference in responses between the 120 placebo-responders and the 79 non-responders. The 79 non-responders' reports showed that if they were considered as an entirely separate group, there was a significant difference the "success rates" of Drugs A, B, and C: viz., 88%, 67%, and 77%, respectively. And because this significant difference in relief from the test drugs could only be attributed to the presence or absence of ingredient b, he concluded that ingredient b was essential (thus contradicting his initial conclusion, derived from the comparison between the "success rates" for all test subjects, that Drugs A, B, and C were equally efficacious).

There were two further repercussions from this trial:

• Jellinek (1946, p.90), having identified 120 "placebo reactors", went on to suppose that all of them may have been suffering from either "psychological headaches" (with or without attendant "hypochondriasis" (p.90)) or "true physiological headaches [which were] accessible to suggestion". Thus, according to this view, the degree to which a "placebo response" is present tends to be an index of the psychogenic origins of the condition in question. (Lasagna et al. 1954, p.777)
• It indicated that, whilst any given placebo was inert, a responder to that particular placebo may be responding for a wide number of reasons unconnected with the drug's active ingredients; and, from this, it could be important to pre-screen potential test populations, and treat those manifesting a placebo-response as a special group, or remove them altogether from the test population.

1983 – cimetidine

This test wrongly seemed to show that cimetidine was a placebo, because they did not know that the bacterium Helicobacter pylori was sometimes present and interfering with results.

Medical anthropologist Daniel Moerman (1983) conducted a meta-study of 31 placebo-controlled trials of the gastric acid secretion inhibitor drug Cimetidine in the treatment of gastric or duodenal ulcers. His meta-study revealed that the placebo treatments were, in many cases, just as effective in treating ulcers as the active drug: of the 1692 patients treated in the 31 trials, 76% of the 916 treated with the drug were "healed", and 48% of the 776 treated with placebo were "healed". These results were confirmed by the direct post-treatment endoscopy of the treated area. He also found that German placebos were "stronger" than others; and that, overall, different physicians evoked quite different placebo responses in the same clinical trial (p.15).

Further examination revealed that many of these trials had been conducted in such a way that the gap between the active drugs and the placebo controls was "not because [the trials' constituents] had high drug effectiveness, but because they had low placebo effectiveness" (p.13).

In some trials, placebos were effective in 90% of the cases, whilst in others the placebos were only effective in 10% of the cases. Moerman argues that "what is demonstrated in [these] studies is not enhanced healing in drug groups, but reduced healing in placebo groups" (p.14).

Moerman also noted the results of two studies (one conducted in Germany, the other in Denmark), which examined "ulcer relapse in healed patients". Each study showed that the rate of relapse amongst those "healed" by the active drug treatment was five times that of those "healed" by the placebo treatment (pp.14–15). This led Moerman to remark: “we may be able to go so far as to say that while [the active drug] “heals” ulcers, placebo treatment can “cure” ulcer disease” (p.14).

These results of a 90% placebo response rate, and a placebo-healed relapse rate 20% that of the active drug seems to indicate that the drug Cimetidine was not effective in inhibiting gastric acid secretion.

However, as we now know, the majority of gastric or duodenal ulcers are not due to excessive gastric acid secretion caused by stress or spicy food, but are due to the bacterium Helicobacter pylori, it is highly significant that this high response rate and low relapse rate can now be interpreted otherwise: it was indicating that the drug's prescribers had chosen the wrong target for their therapeutic intervention (and, as a consequence, we now know that they had chosen what might be termed an "inappropriate target but correct drug", rather than a "correct target but inappropriate drug" as was first supposed).

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 et al. 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.

Examples of effect

In 1938, Diehl, Baker and Cowan reported the results of a study that they had conducted over a two year period into the efficacy of injected vaccines in prevention of colds. Whilst their experimental group showed a significant reduction in the number of colds per person per year, the placebo control group reported the same magnitude of reduction as the vaccinated group. (Diehl et al. 1938, p.1171) This finding was significant, because they also found that their observed level of reduction in the number of colds per person per year matched that of other "uncontrolled studies"; which, given the demonstrated level of placebo responses, meant that "there is no evidence in this study… that vaccines reduce the complications of colds… in a cold-susceptible group". (Diehl et al. 1938, p.1173)

By 1948, the term placebo effect was so widely established that an Egyptian physician could write to The Lancet, reporting that "The success achieved in 83% of cases cannot by any means be ascribed to suggestion or to a placebo effect." (Ayad 1948, p.305)

In 1949, Wolf conducted a series of investigations into the "measurable 'drug effects' that are not attributable to the chemical properties of the agents administered". (Wolf 1950, p.100) Wolf contrasted what he called drug effects with what he called placebo effects.

He noted the extent to which the "[observed] "placebo" actions depended for their force on the conviction of the patient that this or that effect would result". (Wolf 1950, p.106) He drew attention to the impressive frequency and magnitude of these placebo actions and placebo effects and how they could mimic, mask, potentiate, or prevent beneficial responses to the active drugs. He also stressed that all of these placebo actions and placebo effects, "which [modified] the pharmacologic action of drugs or [endowed] inert agents with potency" were associated with real and substantial physiological changes; and, therefore, they were not imaginary. His study also revealed that the action of a drug could be nullified or even reversed in the presence of emotional states such as anger, hostility or resentment.

He also observed that "these effects [were] at times more potent than the pharmacologic action customarily attributed to the [active] agent" (Wolf 1950, p.108–9) and spoke of the well-established understanding "that the mechanisms of the body are capable of reacting not only to direct physical and chemical stimulation but also to symbolic stimuli, words and events which have somehow acquired special meaning for the individual" (Wolf 1950, p.108), in the hope that "in the future drugs will be assessed not only with reference to their pharmacologic action but also to the other [psychodynamic] forces at play and to the circumstances surrounding their administration" (Wolf 1950, p.100).

In 2008, a study showed that the placebo effect was stronger if patients believed that the drug they were given was more expensive compared to a control group who received exactly the same placebo but were told that the drug was very cheap [1].

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 are not the only possible technique for creating "blindness" (= unawareness of the treatment): 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. Beecher misinterpreted his data. Also, Beecher's methodology was very questionable. Then Hróbjartsson & Gøtzsche did two meta-analyses or review of the evidence, and concluded that most of these claims have no basis in the clinical trials published to date^[3][4]. This opinion is widely spread in the placebo literature. 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 does not mean the placebo had an effect. (Put more technically, comparing with the baseline (pretest measure) is vulnerable to the regression fallacy.)

Nevertheless, even they conclude that there might be a small effect for self-reporting outcomes such as pain (this might partly be understood theoretically: Wall, 1999) which, however, is indistinguishable from reporting bias; 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.

Use in clinical trials

Placebo simulators are a standard control component of most clinical trials which attempt to make some sort of quantitative assessment of the efficacy of new medicinal drugs; It is a view held by many "that placebo-controlled studies often are designed in such a way that disadvantages the placebo condition" (Herbert & Gaudiano 2005, p.788–789) and, generally speaking, for a drug to be put on the market, it must be significantly more effective than its placebo counterpart.

According to Yoshioka (1998), the first-ever randomized clinical trial was the trial conducted by the Medical Research Council (1948) into the efficacy of streptomycin in the treatment of pulmonary tuberculosis.There were two test groups in this trial

1. those "treated by streptomycin and bed-rest", and
2. those "[treated] by bed-rest alone" (the control group).

What made this trial exceptional was that the subjects were randomly allocated to their test groups. The up-to-that-time practice was to allocate subjects alternately to each group, based on the order in which they presented for treatment. This practice was considered to be extremely biased, because those admitting each patient knew to which group that patient would be allocated (and it was considered that the decision to admit or not admit a specific patient might be influenced by the experimenter's knowledge of the nature of their illness, and their knowledge of the group to which the alternate allocation demanded they would occupy).

In recent times, the practice of using an additional natural history group as the trial's so-called "third arm" has emerged; and trials are conducted using three randomly selected, equally matched trial groups, David (1949, p.28) wrote: "... it is necessary to remember the adjective ‘random’ [in the term ‘random sample’] should apply to the method of drawing the sample and not to the sample itself.".

1. The Active drug group (A): who receive the active test drug.
2. The Placebo drug group (P): who receive a placebo drug that simulates the active drug.
3. The Natural history group (NH): who receive no treatment of any kind (and whose condition, therefore, is allowed to run its natural course).

The outcomes within each group are observed, and compared with each other, allowing us to measure:

1. The efficacy of the active drug's treatment: the difference between A and NH (i.e., A-NH).
2. The efficacy of the entire treatment process alone: the difference between P and NH (i.e., P-NH).
3. The efficacy of the active drug's active ingredient: the difference between A and P (i.e., A-P).
4. The magnitude of the placebo response: the difference between P and NH (i.e., P-NH).

It is a matter of interpretation whether the value of P-NH indicates the efficacy of the entire treatment process or the magnitude of the "placebo response". The results of these comparisons then determine whether or not a particular drug is considered efficacious.

In recent times, as the demands for the scientific validation of the various claims that are made for the efficacy of various so-called "talking therapies" (such as hypnotherapy, psychotherapy, counseling, and non-drug psychiatry) has significantly increased, there is continuing controversy over what might or might not be an appropriate placebo for such therapeutic treatments. In 2005, the Journal of Clinical Psychology, an eminent peer-reviewed journal (founded in 1945), devoted an entire issue to the question of "The Placebo Concept in Psychotherapy", and contained a wide range of articles that made many valuable contributions to this overall discussion.

Placebo response as an index

In certain clinical trials of particular drugs, it may happen that the level of the "placebo responses" manifested by the trial's subjects are either considerably higher or lower (in relation to the "active" drug's effects) than one would expect from other trials of similar drugs. In these cases, with all other things being equal, it is entirely reasonable to conclude that:

• the degree to which there is a considerably higher level of "placebo response" than one would expect is an index of the degree to which the drug's active ingredient is not efficacious.
• the degree to which there is a considerably lower level of "placebo response" than one would expect is an index of the degree to which, in some particular way, the placebo is not simulating the active drug in an appropriate way.

However, in particular cases such as the use of Cimetidine to treat ulcers (see below), a significant level of placebo response can also prove to be an index of how much the treatment has been directed at a wrong target.

Technical challenges and pitfalls

Preventing subjects from recognizing a placebo

Appropriate use of a placebo in a clinical trial often requires or at least benefits from a double-blind study design, which means that neither the experimenters nor the subjects know which subjects are in the "test group" and which are in the "control group".

Adherence to use of a placebo

The Coronary Drug Project was intended to study the safety and effectiveness of drugs for long-term treatment of coronary heart disease in men. Those in the placebo group who adhered to the placebo treatment (took the placebo regularly as instructed) showed nearly half the mortality rate as those who were not adherent. (Coronary Drug Project 1980) A similar study of women similarly found survival was nearly 2.5 times greater for those who adhered to their placebo. (Gallagher et al. 1993) This apparent placebo effect may be caused by:

• The psychological effect of adhering to the protocol, i.e. genuine placebo effect.
• Being healthy enough to follow the protocol.
• Compliant people being more diligent and scrupulous in all aspects of their lives.

Need for psychoactive placebo

Because a belief that one has received the active drug can produce a markedly heightened placebo effect, it is often necessary to use a psychoactive placebo in clinical trials; i.e., a drug that produces enough physical effects to encourage the belief in the control and experimental groups that they have received the active drug.

A psychoactive placebo was used in the Marsh Chapel Experiment: a double-blind study, in which the experimental group received psilocybin while the control group received a large dose of niacin, a substance that produces noticeable physical effects. Walter Pahnke in 1962 described his Marsh Chapel Experiment in his unpublished Ph.D. dissertation "Drugs and Mysticism: An Analysis of the Relationship between Psychedelic Drugs and the Mystical Consciousness, and submitted it in 1963, for his Ph.D. in Religion and Society at Harvard University; Timothy Leary was the principal academic advisor for his dissertation. In it, Pahnke wrote of administering capsules that contained 30mg of psilocybin extracted from psychoactive mushrooms, and contrasted their effects with those of psychoactive placebos, which contained the chemical niacin in such a dosage that it produced very significant physiological responses. It was intended that these responses would lead the control subjects to believe they had received the psychoactive drug.

The term "psychoactive placebo" is rare in the literature; but, when it is used, it always denotes a placebo of this type. For example, "Neither the experienced investigator nor the naive [subject] is easily fooled on the matter of whether he has received a psychedelic substance or merely a psychoactive placebo such as amphetamine." (Harman et al. 1966, p.215)

Ethical challenges and concerns

Bioethicists have raised diverse concerns on the use of placebos in modern medicine and research. These have been largely incorporated into modern rules for the use of placebos in research but some issues remain subject to debate. 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 Gøtzsche^[3][4] and others, the proposition that placebos may do some good is under fire.

• Disclosure. Rules that govern modern clinical trials insist on full disclosure to subjects who take part. Today, subjects are told that they may receive the drug being tested or they may receive the placebo.
• Balancing Treatment vs. Research Objectives. Ethicists have also raised concerns on the use of placebos in those circumstances in which a standard treatment exists unless there are genuine doubts of the effectivity of such standard treatment. If standard treatments exist for the disease being studied in clinical trials, a standard treatment is always used in place of a placebo for serious diseases. 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.

Most of these concerns have been addressed in the modern conventions for the use of placebos in research; however, some issues remain subject to debate.

From the time of the Hippocratic Oath questions of the ethics of medical practice have been widely discussed, and codes of practice have been gradually developed as a response to advances in scientific medicine. The Nuremberg Code, which was issued in August 1947, as a consequence of the so-called Doctors' Trial which examined the human experimentation conducted by Nazi doctors during World War II, offers ten principles for legitimate medical research, including informed consent, absence of coercion, and beneficence towards experiment participants.

In 1964, the World Medical Association issued the Declaration of Helsinki,[2] which specifically limited its directives to health research by physicians, and emphasized a number of additional conditions in circumstances where "medical research is combined with medical care". The significant difference between the 1947 Nuremberg Code and the 1964 Declaration of Helsinki is that the first was a set of principles that was suggested to the medical profession by the "Doctors’ Trial" judges, whilst the second was imposed by the medical profession upon itself. Paragraph 29 of the Declaration makes specific mention of placebos:

29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.

In 2002, World Medical Association issued the following elaborative announcement:

Note of clarification on paragraph 29 of the WMA Declaration of Helsinki

The WMA hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled trial and that in general this methodology should only be used in the absence of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:

— Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or

— Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.

All other provisions of the Declaration of Helsinki must be adhered to, especially the need for appropriate ethical and scientific review.

In addition to the requirement for informed consent from all drug-trial participants, it is also standard practice to inform all test subjects that they may receive the drug being tested or that they may receive the placebo.

See also

External links

• The Placebo Effect at the Skeptic's Dictionary
• The Placebo Effect explained on YouTube

References

Books

History of medicine

Modern research

General audience