Placebo controlled trials are those trials where some participants take a placebo as a control and the others take the drug being investigated. Here the placebo is an inactive substance designed to resemble the drug being tested. It is used as a control to rule out any psychological effects which may show during testing. Most well-designed studies include a control group which is unwittingly taking a placebo.
The placebo effect or placebo response is a therapeutic or healing effect of an inert medicine or ineffective therapy, or more generally is the psychosocial aspect of every medical treatment. Sometimes known as a non-specific effect or subject-expectancy effect, the placebo effect (or its counterpart, the nocebo effect), occurs when a patient's symptoms are altered in some way (i.e., alleviated or exacerbated) by a treatment, due to the individual expecting or believing that it will work. The placebo effect occurs when a patient is treated in conjunction with the suggestion from an authority figure or from acquired information that the treatment will aid in healing and the patient’s condition improves. This effect has been observed since the early 20th century.
The word placebo has been used in with various meanings; see below.
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.
The word Obecalp, "placebo" spelled backwards was coined by an Australian doctor in 1998 when he recognised the need for a freely available placebo. The word is sometimes used to make the use or prescription of fake medicine less obvious to the patient.
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.)
Placebos are inactive 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. (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. One can see this clearly in the reaction of children to the administration of care by their mothers. The bandaide does, in fact, make the pain go away.
Placebos are, therefore, 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. There is intensive research in this area. According to Shapiro:
The editorial suggested there were problems with the methods of the study by Hróbjartsson and Gøtzsche (see below under Objective and subjective effects) 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 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.
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 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:
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.
In the 1930s Evans & Hoyle (1933), using 90 subjects, and Gold, Kwit and Otto (1937), 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 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".
This is true as well for the "sugar pill." People who believe they are sick but do not have an observable cause of the problem can actually develop the symptoms of the illness. Some doctors have given such patients a basic sugar cube disguised as a regular tablet of medicine. The patient assumed what they were taking would make them feel better and it did.
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)
The following are some of the issues pointing to a fundamental problem:
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:
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 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:
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:
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..." 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.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.
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.
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." 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)
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" (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":
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".
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 Naval Surgeon 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:
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.
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:
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". (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:
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.
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
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 (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.
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:
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, 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.
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.
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)
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, 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:
In 2002, World Medical Association issued the following elaborative announcement:
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.
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