placebo-controlled study placebo-controlled study placebo-controlled studies are a way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate control group receives a sham "placebo" treatment which is specifically designed to have no real effect. placebos are most commonly used in blinded trials, where subjects do not know whether they are receiving real or placebo treatment. often, there is also a further "natural history" group that does not receive any treatment at all. prescription placebos used in research and practice the purpose of the placebo group is to account for the placebo effect, that is, effects from treatment that do not depend on the treatment itself. such factors include knowing one is receiving a treatment, attention from health care professionals, and the expectations of a treatment's effectiveness by those running the research study. without a placebo group to compare against, it is not possible to know whether the treatment itself had any effect. patients frequently show improvement even when given a sham or "fake" treatment. such intentionally inert placebo treatments can take many forms, such as a pill containing only sugar, a surgery where nothing efficacious is actually done (just an incision and sometimes some minor touching or handling of the underlying structures), or a medical device (such as an ultrasound machine) that is not actually turned on. also, due to the body's natural healing ability and statistical effects such as regression to the mean, many patients will get better even when given no treatment at all. thus, the relevant question when assessing a treatment is not "does the treatment work?" but "does the treatment work better than a placebo treatment, or no treatment at all?" as one early clinical trial researcher 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."p.195 more broadly, the aim of a clinical trial is to determine what treatments, delivered in what circumstances, to which patients, in what conditions, are the most effective. therefore, the use of placebos is a standard control component of most clinical trials, which attempt to make some sort of quantitative assessment of the efficacy of medicinal drugs or treatments. such a test or clinical trial is called a placebo-controlled study, and its control is of the negative type. a study whose control is a previously tested treatment, rather than no treatment, is called a positive-control study, because its control is of the positive type. 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). this close association of placebo effects with rcts has a profound impact on how placebo effects are understood and valued in the scientific community. methodology blinding main article: blinded experiment blinding is the withholding of information from participants which may influence them in some way until after the experiment is complete. good blinding may reduce or eliminate experimental biases such as confirmation bias, the placebo effect, the observer effect, and others. a blind can be imposed on any participant of an experiment, including subjects, researchers, technicians, data analysts, and evaluators. in some cases, while blinding would be useful, it is impossible or unethical. for example, is not possible to blind a patient to their treatment in a physical therapy intervention. a good clinical protocol ensures that blinding is as effective as possible within ethical and practical constrains. during the course of an experiment, a participant becomes unblinded if they deduce or otherwise obtain information that has been masked to them. unblinding that occurs before the conclusion of a study is a source of experimental error, as the bias that was eliminated by blinding is re-introduced. unblinding is common in blind experiments, and must be measured and reported. natural history groups 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, reilly wrote: "... it is necessary to remember the adjective 'random' should apply to the method of drawing the sample and not to the sample itself." the active drug group (a): who receive the active test drug. the placebo drug group (p): who receive a placebo drug that simulates the active drug. the natural history group (nh): who receive no treatment of any kind (and whose condition, therefore, is allowed to run its natural course). the outcomes within each group are observed, and compared with each other, allowing us to measure: the efficacy of the active drug's treatment: the difference between a and nh (i.e., a-nh). the efficacy of the active drug's active ingredient: the difference between a and p (i.e., a-p). the magnitude of the placebo response: the difference between p and nh (i.e., p-nh). it is a matter of interpretation whether the value of p-nh indicates the efficacy of the entire treatment process or the magnitude of the "placebo response". the results of these comparisons then determine whether or not a particular drug is considered efficacious. natural-history groups yield useful information when separate groups of subjects are used in a parallel or longitudinal study design. in crossover studies, however, where each subject undergoes both treatments in succession, the natural history of the chronic condition under investigation (e.g., progression) is well understood, with the study's duration being chosen such that the condition's intensity will be more or less stable over that duration. (wang et al. provide the example of late-phase diabetes, whose natural history is long enough that even a crossover study lasting one year is acceptable.) in these circumstances, a natural history group is not expected to yield useful information. indexing 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 reasonable to conclude that: the degree to which there is a considerably higher level of "placebo response" than one would expect is an index of the degree to which the drug's active ingredient is not efficacious. the degree to which there is a considerably lower level of "placebo response" than one would expect is an index of the degree to which, in some particular way, the placebo is not simulating the active drug in an appropriate way. however, in particular cases such as the use of cimetidine to treat ulcers, 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. implementation issues adherence the coronary drug project was intended to study the safety and effectiveness of drugs for long-term treatment of coronary heart disease in men. those in the placebo group who adhered to the placebo treatment (took the placebo regularly as instructed) showed nearly half the mortality rate as those who were not adherent. 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 have occurred because: adhering to the protocol had a psychological effect, i.e. genuine placebo effect. people who were already healthier were more able or more inclined to follow the protocol. compliant people were more diligent and health-conscious in all aspects of their lives. unblinding main article: unblinding in some cases, a study participant may deduce or otherwise obtain information that has been blinded to them. for example, a patient taking a psychoactive drug may recognize that they are taking a drug. when this occurs, it is called unblinding. this kind of unblinding can be reduced with the use of an active placebo, which is a drug that produces effects similar to the active drug, making it more difficult for patients to determine which group they are in. an active placebo was used in the marsh chapel experiment, a blinded study in which the experimental group received the psychedelic substance psilocybin while the control group received a large dose of niacin, a substance that produces noticeable physical effects intended to lead the control subjects to believe they had received the psychoactive drug. history james lind and scurvy a portrait of scottish doctor james lind (1716–1794)in 1747, james lind (1716–1794), the ship's doctor on hms salisbury, conducted the first 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. 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: one quart of cider per day, twenty-five drops of elixir vitriol (sulfuric acid) three times a day, two spoonfuls of vinegar three times a day, a course of sea-water (half a pint every day), two oranges and one lemon each day, and electuary, (a mixture containing garlic, mustard, balsam of peru, and myrrh). 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. animal magnetism in 1784, the french royal commission investigated the existence of animal magnetism, comparing the effects of 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 (1739–1786). 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, and published his findings in a book on the imagination as a cause & as a cure of disorders of the body. flint and placebo active treatment comparison 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 disease".: 18 flint's paper is the first time that he terms "placebo" or "placeboic remedy" were 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: 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.: 32–34 in the thirteenth case, flint expressed some doubt 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".: 36 jellinek and headache remedy ingredients jellinek in 1946 was asked to test whether or not the headache drug's overall efficacy would be reduced if certain ingredients were removed. in post-world war ii 1946, pharmaceutical chemicals were restricted, and one u.s. headache remedy manufacturer sold a drug composed of