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Sometimes known as non-specific effects or subject-expectancy effects, a so-called placebo effect occurs when a patient's symptoms are altered in some way (i.e., alleviated or exacerbated) by an otherwise inert treatment, due to the individual expecting or believing that it will work.
The placebo effect occurs when a patient takes an inert substance (a "sugar pill") in conjunction with the suggestion from an authority figure that the pill will aid in healing and the patient’s condition improves. This effect has been known for years.
The word "placebo" has been used in many somewhat varying meanings; see below.
Additional recommended knowledge
The concept of placebo
It has been observed often enough, yet still frequently overlooked, that the notion of placebo as it occurs in modern clinical discourse is not a rigorous concept, and despite many attempts, it has not been possible to provide a coherent definition. The most cited one is probably that of Arthur Shapiro, which together with others in the same vein, makes use of the idea of "non-specific" therapeutic effects, and thus merely shifts the explanatory burden to this equally undefined concept. In addition, as Moerman has pointed out, such definitions assert at the same time that placebos are inert and that they produce the placebo effect, which is self-contradictory. In a detailed critique of Shapiro's approach, Grunbaum attempted to formulate a logically consistent definition, but this in turn has been criticized on the grounds that it is uninformative in respect of the phenomenon itself – that is, the behaviour in a clinical setting of patients, bodies, physicians, and therapeutic maneuvers. In the view of Moerman and others, clinical science has burdened itself with a pseudo-concept, more confusing than useful, the correction of which will entail a revision of some foundational thinking in clinical medicine.
Recent studies published in Proceedings of the National Academy of Sciences using advances in neuroscience (PET scans) have shown that placebos can demonstrably 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. 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 for years. 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.
The following are some of the issues pointing to a fundamental problem:
Although placebos are generally characterized as pharmacologically inert substances or formulations, sham treatments, or inactive procedures, they are only inert, sham, ineffective, or inactive in the particular sense that they have no known cause and effect relationship with any of the pre-designated, biochemical, physiological, behavioural, emotional and/or cognitive outcomes of the pharmacologically active and known-to-be-efficacious intervention that might have otherwise been applied (see below).
Placebos are inactive or ineffective treatments or formulations; however a patient may experience either a positive or negative clinical effect while taking one. When a placebo is administered to mimic a previously administered drug, it may also incur the same side effects as the prior authentic drug. Most of these effects are thought to be psychological in nature or due to other unrelated factors. Not all placebos are equally effective. A placebo that involves ingestion, injection, or incision is often more powerful than a non-invasive technique. Placebos administered by authority figures such as general practitioners and other experts may also be more powerful than when this psychological authority effect is absent.
They are, however, not inert, sham, or inactive in any other manner of speaking; and they may well, in and of themselves, generate considerable change within any given subject, at any given time, under any given circumstances. According to Shapiro:
Actually the question of inert versus active placebo is academic, because there is no such thing as an inactive substance. For example, distilled water injections can cause hemolysis and water intoxication. Ingestion of two 5-grain [325 mg] capsules of sacchari lactis [milk sugar], QID [quater in die, "four times a day"], for 30 years, can result in a weight gain of 30 pounds, so that even sugar can hardly be considered harmless, indifferent, or inert.
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 her or his ability to get well, or even purely coincidental worsening of symptoms.
The word placebo is Latin for "I will please". It is in Latin text in the Bible (Psalm 114:1–9, Vulgate version), from where it became familiar to the public via the Office of the Dead church service (see Placebo (at funeral) for details).
Whenever a placebo is requested in a medical prescription it may imply a statement by the prescribing doctor that "This patient has come to me pleading for a treatment which does not exist or which I cannot or will not supply; I will please him by giving him something ineffectual and claiming that it is effectual." It could also indicate a belief that the effect was due to a subconscious desire of the patient to please the doctor. Since the placebo effect is in the patient not the doctor this may be more self-consistent. Early usage of the term does not indicate why it was chosen.
Sometimes a doctor who does this, says that the fake medicine is `Obecalp', which is "placebo" spelled backwards.   (and many other links)
Early use of placebos
Originally, a placebo was a substance that a well-meaning doctor would give to a patient, telling him that it was a powerful drug (e.g., a painkiller), when in fact it was nothing more than a sugar pill. Thus, Hooper's medical dictionary of 1811 says placebo is "an epithet given to any medicine adapted more to please than benefit the patient." The subsequent reduction of the patient's symptoms was attributed to the patient's faith in his doctor and hence his belief in the drug. (This category, particularly before the first Medicines Act was passed, may merge into fake medicines.)
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.
Origin of term "placebo effect" (1920)
Perhaps Graves (1920) was the first to speak of the placebo effect, when he spoke of "the placebo effects of drugs" being manifested in those cases where "a real psychotherapeutic effect appears to have been produced".
In 1933 (Evans and Hoyle) (using 90 subjects) and in 1937 (Gold, Kwit and Otto) (using 700 subjects) each published a study 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 speak of either a "placebo reaction" or a "placebo response". He speaks 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). From this, it is obvious that, to Jellinek, the terms "placebo response" and "placebo reaction"—or the terms "placebo responder" and "placebo reactor"—were identical and interchangeable.
The general literature commonly misattributes 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, Keats, Mosteller, and Lasagna (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".
Isolation of causation
According to Kleijnen and his colleagues, healing is an interactive process between three influences:
These effects are not isolated mutually-exclusive effects and, rather than just adding, they may help or hinder each other to various degrees. 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:
In pursuit of establishing causation, the question “Who does what, with which, and to whom?” is central to task of identifying what are:
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 & Otto (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:
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:
Technical challenges and pitfalls
Preventing subjects recognizing 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 placebo
The Coronary Drug Project was intended to study the safety and effectiveness of safety 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. A similar study of women similarly found survival was nearly 2.5 times greater for those who adhered to their placebo. This apparent placebo effect may be caused by:
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 contrasting 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, McKim, Mogar, Fadiman & Stolaroff, 1966, p.215)
Placebos 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" 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
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.".
The outcomes within each group are observed, and compared with each other, allowing us to measure:
Note that, depending upon the focus of your interest, the value of P-NH can either indicate 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, counselling, 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.
The 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:
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.
"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:
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, or are intentionally efficacious and also specific.
Gaddum (1953, 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."
Citrus fruit and scurvy (1747)
In 1747, James Lind (1716–1794), the Naval Surgeon on HMAS 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.
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:
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.
Animal magnetism (1784)
In 1784, the French Royal Commission into the existence of animal magnetism investigated the practices of Charles d’Eslon (1739–1786) and compared the effects of his allegedly "magnetized" water with that of plain water.
It did not examine the practices of Franz Mesmer, but examined the significantly different practices of his associate Charles d’Eslon.
See animal magnetism for more information.
Perkins tractors (1799)
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.
Diluted quassia as placebo (1863)
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’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).
Mercury for syphilis
Treatment of syphilis with salves made from mercury, proved to have no medical effect.
A headache remedy (1946)
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:
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:
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".
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:
Cimetidine and stomach ulcers (1983)
In 1983 medical anthropologist Daniel Moerman 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).
Beecher (1955) reported that about a quarter of patients who were administered a placebo, for example against back pain, reported a relief or diminution of pain. Remarkably, not only did the patients report improvement, but the improvements themselves were often objectively measurable, and the same improvements were typically not observed in patients who did not receive the placebo.
Because of this effect, government regulatory agencies approve new drugs only after tests establish not only that patients respond to them, but also that their effect is greater than that of a placebo (by way of affecting more patients, by affecting responders more strongly or both). Such a test or clinical trial is called a placebo-controlled study.
Because a doctor's belief in the value of a treatment can affect his or her behaviour, and thus what his or her patient believes, such trials are usually conducted in "double-blind" fashion: that is, not only are the patients made unaware when they are receiving a placebo, the doctors are made unaware too. Recently, it has even been shown that "mock" surgery can have similar effects, and so some surgical techniques must be studied with placebo controls (rarely double blind, due to the difficulty involved). To merit approval, the group receiving the experimental treatment must experience a greater benefit than the placebo group.
Nearly all studies conducted this way show some benefit in the placebo group. For example, Khan published a meta-analysis of studies of investigational antidepressants and found a 30% reduction in suicide and attempted suicide in the placebo groups and a 40% reduction in the treated groups. (Khan 2000) However, studies generally do not include an untreated group, so determining the actual size of the placebo effect, compared to totally untreated patients, is difficult.
Placebo effect on various symptoms
Placebo and pain
Careful studies have shown that the placebo effect can alleviate pain, although the effect is more pronounced with pre-existing pain than with experimentally induced pain. People can be conditioned to expect analgesia in certain situations. When those conditions are provided to the patient, the brain responds by generating a pattern of neural activity that produces objectively quantifiable analgesia. (Benedetti 2003, Wager 2004)
Evans argued that the placebo effect works through a suppression of the acute phase response, and as a result does not work in medical conditions that do not feature this. (Evans 2005) The acute phase response consists of inflammation and sickness behaviour:
Placebo and depression
A brain-imaging study found that depressed patients who responded to the placebo effect showed changes in cerebral blood flow, which were similar to the changes in brain function seen in patients who responded to anti-depressant medication. (Leuchter 2002) Other studies argue that up to 75% of the effectiveness of anti-depressant medication is due to the placebo-effect rather than the treatment itself. (Khan 2000)
Withdrawal symptoms on discontinuance of placebo
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). Only the vasomotor symptoms (hot flashes/night sweats) were acknowledged to be verified effects of menopause by a 2005 National Institutes of Health panel.
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 or subjective effects?
Hrobjartsson and Götzsche published a study in 2001 and a follow-up study in 2004 questioning the nature of the placebo effect. (Hrobjartsson 2001, Hrobjartsson 2004) They performed two meta-analyses involving 156 clinical trials in which an experimental drug or treatment protocol was compared to a placebo group and an untreated group, and specifically asked whether the placebo group improved compared to the untreated group. Hrobjartsson and Götzsche found that in studies with a binary outcome, meaning patients were classified as improved or not improved, the placebo group had no statistically significant improvement over the no-treatment group. Similarly, there was no significant placebo effect in studies in which objective outcomes (such as blood pressure) were measured by an independent observer. The placebo effect could only be documented in studies in which the outcomes (improvement or failure to improve) were reported by the subjects themselves. The authors concluded that the placebo effect does not have "powerful clinical effects," (objective effects) and that patient-reported improvements (subjective effects) in pain were small and could not be clearly distinguished from bias.
These results suggest that the placebo effect is largely subjective. This would help explain why the placebo effect is easiest to demonstrate in conditions where subjective factors are very prominent or significant parts of the problem. Some of these conditions are headache, stomachache, asthma, allergy, tension, and the experience of pain, which is often a significant part of many mild and serious illnesses.
How the placebo effect works
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, but must not know it is an ineffective placebo. 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.
The subject-expectancy effect attributes the placebo effect to conscious or unconscious manipulation by patients in reporting improvement. Hrobjartsson and Götzsche argued in their article, "Most patients are polite and prone to please the investigators by reporting improvement, even when no improvement was felt." Subjective bias can also be unconscious, where the patient believes he is improving as a result of the attention and care he has received.
Classical conditioning is a type of associative learning where the subject learns to associate a particular stimulus with a particular response. In this case the stimulant is the substance perceived as medicine but is the placebo, and the response is the relief of symptoms. It is difficult to tell the difference between conditioning and the expectancy effect when the outcome is subjective and reported by the patient. However, conditioning can result in measurable biological changes similar to the changes seen with the real treatment or drug. For example, studies showing that placebo treatments result in changes in brain function similar to the real drug are probably examples of conditioning resulting in objectively measurable results. (Sauro 2005, Wager 2004, Arnaldo 2002)
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.
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 that we can enhance their effectiveness and convert their potential efficacy into actual relief, healing and cure.
Recent research 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"; 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":
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"). This supports the claim that there are unconscious brain processes that activate the "placebo response".
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 Götzsche and others, the proposition that placebos may do some good is under fire.
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 outrageous 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, 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
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.
A Danish study of placebos
A study of Danish general practitioners found that 48% had prescribed a placebo at least 10 times in the past year. The most frequently prescribed placebos were antibiotics for viral infections, and vitamins for fatigue. Specialists and hospital-based physicians reported much lower rates of placebo use. (Hrobjartsson 2003) A 2004 study in the British Medical Journal of physicians in Israel found that 60% used placebos in their medical practice, most commonly to "fend off" requests for unjustified medications or to calm a patient. Of the physicians who reported using placebos, only 15% told their patients they were receiving placebos or non-specific medications. (Nitzan 2004) An accompanying editorial stated,
The placebo effect, thought of as the result of the inert pill, can be better understood as an effect of the relationship between doctor and patient. Adding the doctor's caring to medical care affects the patient's experience of treatment, reduces pain, and may affect outcome. This survey makes it clear that doctors continue to use placebos, and most think they help.
The editorial suggested there were problems with Hróbjartsson and Götzsche's methods and argued that their results show that placebos can't cure everything, but don't prove that the placebo effect cures nothing. The editorial concluded, "We cannot afford to dispense with any treatment that works, even if we are not certain how it does." (Spiegel 2004)
The editorial prompted responses on both sides of the issue.
BMJ posted a series of responses to Dr. 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:
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 they (those not in delirium) are told that are being given a powerful dose of painkiller.
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.
Placebos 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 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". 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 -- 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 naturæ (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:
A "placebo" as "something useless"
Useless decoctions, drugs, treatments, remedies, and procedures are given the pejorative label placebo.
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.
Examples of placebo 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. 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-susceptiible group".
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."
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 contrasting 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". 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". 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", 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".
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 Hrobjartsson & Gotzsche (2001) did a meta-analysis or review of the evidence, and concluded that most of these claims have no basis in the clinical trials published to date. This opinion is widely spread in the placebo literature. The chief points of their skeptical argument are:
Nevertheless, even they conclude that there is a real placebo effect for pain (not surprising since this is partly understood theoretically: Wall, 1999)); and for some other continuously-valued subjectively-assessed effects. A recent experimental demonstration was reported: Zubieta et al. (2005) "Endogenous Opiates and the Placebo Effect" The journal of neuroscience vol.25 no.34 p.7754–7762
This seems to show that the psychological cause (belief that the placebo treatment might be effective in reducing pain) causes opioid release in the brain, which then presumably operates in an analogous way to externally administered morphine.
A recent and more extensive review of the overall dispute is: M. Nimmo (2005) Placebo: Real, Imagined or Expected? A Critical Experimental Exploration Final year undergraduate Critical Review, Dept. of Psychology, University of Glasgow. PDF copy.
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