Placebo-controlled studies - AbsoluteAstronomy.com

A Placebo-controlled study is 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

Scientific control

Scientific control allows for comparisons of concepts. It is a part of the scientific method. Scientific control is often used in discussion of natural experiments. For instance, during drug testing, scientists will try to control two groups to keep them as identical and normal as possible, then...

group receives a sham "placebo

Placebo

A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...

" 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.

The purpose of the placebo group is to account for the placebo effect

Placebo effect

Placebo effect may refer to:* Placebo effect, the tendency of any medication or treatment, even an inert or ineffective one, to exhibit results simply because the recipient believes that it will work...

, 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.

Overview

Patients frequently show improvement even when given a sham or "fake" treatment. Such intentionally inert placebo

Placebo

A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...

treatments can take many forms, such as a pill containing only sugar, a surgery where nothing is actually done, or a medical device (such as ultrasound) 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

Clinical trial

Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

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." More broadly, the aim of a clinical trial

Clinical trial

Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

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

Scientific control

component of most clinical trial

Clinical trial

Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

s which attempt to make some sort of quantitative

Quantitative property

A quantitative property is one that exists in a range of magnitudes, and can therefore be measured with a number. Measurements of any particular quantitative property are expressed as a specific quantity, referred to as a unit, multiplied by a number. Examples of physical quantities are distance,...

assessment of the efficacy of medicinal drugs or treatments. Such a test or clinical trial

Clinical trial

Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

is called a placebo-controlled study.

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). As a result, "placebo-controlled studies often are designed in such a way that disadvantages the placebo condition".

Blind trials

Things like sugar pills, that look like real treatments but in fact have no physical effect 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. Blind trials control all of these 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

Prayer

Prayer is a form of religious practice that seeks to activate a volitional rapport to a deity through deliberate practice. Prayer may be either individual or communal and take place in public or in private. It may involve the use of words or song. When language is used, prayer may take the form of...

by others, the participants are not told who has and has not had prayers said for them. To test the effect of changing the frequency of fluorescent lights on headache

Headache

A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...

s, the light fittings are changed at night in the absence of the office workers (this is a real case). It has 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).

Double-blind trials

Because a doctor's belief in the value of a treatment can affect his or her behavior, and thus what his or her patient believes, clinical trials are usually conducted in "double-blind

Double-blind

A blind or blinded experiment is a scientific experiment where some of the people involved are prevented from knowing certain information that might lead to conscious or subconscious bias on their part, invalidating the results....

" manner: that is, not only are the patients made unaware when they are receiving a placebo, the doctors are made unaware too.

Nearly all studies conducted find benefit in the placebo group. For example, Khan published a meta-analysis

Meta-analysis

In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...

of studies of investigational antidepressant

Antidepressant

An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...

s and found a 30% reduction in suicide and attempted suicide in the placebo groups and a 40% reduction in the treated groups. 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.

Natural history groups

The practice of using an additional natural history group

Natural history group

The term natural history group refers to subjects in a drug trial that receive no treatment of any kind and whose illness is, as a consequence, left to run its "natural" course...

as the trial's so-called "third arm" has emerged; and trials are conducted using three randomly selected, equally matched trial groups, David 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 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.

"Talking therapies" (such as hypnotherapy

Hypnotherapy

Hypnotherapy is a therapy that is undertaken with a subject in hypnosis.The word "hypnosis" is an abbreviation of James Braid's term "neuro-hypnotism", meaning "sleep of the nervous system"....

, psychotherapy

Psychotherapy

Psychotherapy is a general term referring to any form of therapeutic interaction or treatment contracted between a trained professional and a client or patient; family, couple or group...

, counseling, and non-drug psychiatry

Psychiatry

Psychiatry is the medical specialty devoted to the study and treatment of mental disorders. These mental disorders include various affective, behavioural, cognitive and perceptual abnormalities...

) are now required to have scientific validation

Validation

Validation or validity may refer to:* Validity, in logic, determining whether a statement is true or false* Validity , the application of the principles of statistics to arrive at valid conclusions...

by clinical trial. However, there is controversy over what might or might not be an appropriate placebo for such therapeutic treatments. In 2005, the Journal of Clinical Psychology, devoted an issue to the issue of "The Placebo Concept in Psychotherapy" that contained a range of contributions to this question.

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

Ceteris paribus

or is a Latin phrase, literally translated as "with other things the same," or "all other things being equal or held constant." It is an example of an ablative absolute and is commonly rendered in English as "all other things being equal." A prediction, or a statement about causal or logical...

, 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.

Placebo ingredients

Placebos used in clinical trials have sometimes had unintended consequences. A report in the Annals of Internal Medicine that looked at details from 150 clinical trials, found that certain placebos used in the trials effected the results. For example, one study on cholesterol-lowering drugs used olive oil

Olive oil

Olive oil is an oil obtained from the olive , a traditional tree crop of the Mediterranean Basin. It is commonly used in cooking, cosmetics, pharmaceuticals, and soaps and as a fuel for traditional oil lamps...

and corn oil

Corn oil

Corn oil is oil extracted from the germ of corn . Its main use is in cooking, where its high smoke point makes refined corn oil a valuable frying oil. It is also a key ingredient in some margarines. Corn oil is generally less expensive than most other types of vegetable oils. One bushel of corn...

in the placebo pills. However, according to the report, this "may lead to an understatement of drug benefit: The monounsaturated and polyunsaturated fatty acids of these 'placebos,' and their antioxidant and anti-inflammatory effects, can reduce lipid levels and heart disease." Another example researchers reported in the study was a clinical trial of a new therapy for cancer patients suffering from anorexia

Anorexia (symptom)

Anorexia is the decreased sensation of appetite...

. The placebo that was used included lactose

Lactose

Lactose is a disaccharide sugar that is found most notably in milk and is formed from galactose and glucose. Lactose makes up around 2~8% of milk , although the amount varies among species and individuals. It is extracted from sweet or sour whey. The name comes from or , the Latin word for milk,...

. However, since cancer patients typically face a higher risk of lactose intolerance

Lactose intolerance

Lactose intolerance, also called lactase deficiency or hypolactasia, is the inability to digest and metabolize lactose, a sugar found in milk...

, the placebo pill might actually have caused unintended side effects that made the experimental drug look better in comparison.

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

Mortality rate

Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...

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.

Placebo recognition

Appropriate use of a placebo in a clinical trial

Clinical trial

Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

often requires or at least benefits from a double-blind

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". This creates a problem in creating placebos that can be mistaken for active treatments. It therefore can be necessary to use a psychoactive placebo, a drug that produces physiological effects that encourage the belief in the control groups that they have received an active drug.

A psychoactive placebo was used in the Marsh Chapel Experiment

Marsh Chapel Experiment

The Marsh Chapel Experiment was run by Walter N. Pahnke, a graduate student in theology at Harvard Divinity School, under the supervision of Timothy Leary and the Harvard Psilocybin Project. The goal was to see if in religiously predisposed subjects, psilocybin would act as reliable entheogen...

, a double-blind

Double-blind

study in which the experimental group received the psychedelic

Psychedelic

The term psychedelic is derived from the Greek words ψυχή and δηλοῦν , translating to "soul-manifesting". A psychedelic experience is characterized by the striking perception of aspects of one's mind previously unknown, or by the creative exuberance of the mind liberated from its ostensibly...

substance psilocybin

Psilocybin

Psilocybin is a naturally occurring psychedelic prodrug, with mind-altering effects similar to those of LSD and mescaline, after it is converted to psilocin. The effects can include altered thinking processes, perceptual distortions, an altered sense of time, and spiritual experiences, as well as...

while the control group received a large dose of niacin

Niacin

"Niacin" redirects here. For the neo-fusion band, see Niacin .Niacin is an organic compound with the formula and, depending on the definition used, one of the forty to eighty essential human nutrients.Niacin is one of five vitamins associated with a pandemic deficiency disease: niacin deficiency...

, a substance that produces noticeable physical effects intended to 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
Psychedelic
The term psychedelic is derived from the Greek words ψυχή and δηλοῦν , translating to "soul-manifesting". A psychedelic experience is characterized by the striking perception of aspects of one's mind previously unknown, or by the creative exuberance of the mind liberated from its ostensibly...

substance or merely a psychoactive placebo such as amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...

."

James Lind and scurvy

In 1747, James Lind (1716–1794), the ship's doctor

Ship's doctor

A Ship's doctor or Ship's surgeon is the person responsible for the health of the people aboard a ship whilst at sea. The term "ship's doctor" or "ship's surgeon" appears often in reference to the Age of Sail British Royal Navy's "surgeons." These men, like other physicians, often did not have much...

on HMS Salisbury

HMS Salisbury

Seven ships of the Royal Navy have been named HMS Salisbury after the city of Salisbury in Wiltshire:* HMS Salisbury was a 48-gun fourth rate, launched in 1698 and captured by the French in 1703. She was subsequently recaptured in 1708 and renamed Salisbury Prize, and later renamed Preston in 1716...

, conducted the first clinical trial

Clinical trial

Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

when he investigated the efficacy of citrus fruit in cases of scurvy

Scurvy

Scurvy is a disease resulting from a deficiency of vitamin C, which is required for the synthesis of collagen in humans. The chemical name for vitamin C, ascorbic acid, is derived from the Latin name of scurvy, scorbutus, which also provides the adjective scorbutic...

. 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

Cider

Cider or cyder is a fermented alcoholic beverage made from apple juice. Cider varies in alcohol content from 2% abv to 8.5% abv or more in traditional English ciders. In some regions, such as Germany and America, cider may be termed "apple wine"...

per day, twenty-five drops of elixir vitriol (sulfuric acid

Sulfuric acid

Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...

) three times a day, two spoonfuls of vinegar

Vinegar

Vinegar is a liquid substance consisting mainly of acetic acid and water, the acetic acid being produced through the fermentation of ethanol by acetic acid bacteria. Commercial vinegar is produced either by fast or slow fermentation processes. Slow methods generally are used with traditional...

three times a day, a course of sea-water (half a pint

Pint

The pint is a unit of volume or capacity that was once used across much of Europe with values varying from state to state from less than half a litre to over one litre. Within continental Europe, the pint was replaced with the metric system during the nineteenth century...

every day), two orange

Orange (fruit)

An orange—specifically, the sweet orange—is the citrus Citrus × sinensis and its fruit. It is the most commonly grown tree fruit in the world....

s and one lemon

Lemon

The lemon is both a small evergreen tree native to Asia, and the tree's ellipsoidal yellow fruit. The fruit is used for culinary and non-culinary purposes throughout the world – primarily for its juice, though the pulp and rind are also used, mainly in cooking and baking...

each day, and electuary

Electuary

An electuary is a medicinal paste composed of powders, or other medical ingredients, incorporated with sweeteners to hide the taste, like syrup, honey, jam, etc., for the purposes of oral consumption....

, (a mixture containing garlic

Garlic

Allium sativum, commonly known as garlic, is a species in the onion genus, Allium. Its close relatives include the onion, shallot, leek, chive, and rakkyo. Dating back over 6,000 years, garlic is native to central Asia, and has long been a staple in the Mediterranean region, as well as a frequent...

, mustard

Mustard (condiment)

Mustard is a condiment made from the seeds of a mustard plant...

, balsam of Peru, and myrrh

Myrrh

Myrrh is the aromatic oleoresin of a number of small, thorny tree species of the genus Commiphora, which grow in dry, stony soil. An oleoresin is a natural blend of an essential oil and a resin. Myrrh resin is a natural gum....

).

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

Royal Commission

In Commonwealth realms and other monarchies a Royal Commission is a major ad-hoc formal public inquiry into a defined issue. They have been held in various countries such as the United Kingdom, Australia, Canada, New Zealand, and Saudi Arabia...

looked into the existence of animal magnetism

Animal magnetism

Animal magnetism , in modern usage, refers to a person's sexual attractiveness or raw charisma. As postulated by Franz Mesmer in the 18th century, the term referred to a supposed magnetic fluid or ethereal medium believed to reside in the bodies of animate beings...

, comparing the effects of allegedly "magnetized" water with that of plain water.
It did not examine the practices of Franz Mesmer

Franz Mesmer

Franz Anton Mesmer , sometimes, albeit incorrectly, referred to as Friedrich Anton Mesmer, was a German physician with an interest in astronomy, who theorised that there was a natural energetic transference that occurred between all animated and inanimate objects that he called magnétisme animal ...

, but examined the significantly different practices of his associate Charles d'Eslon (1739–1786).

Perkins tractors

In 1799, John Haygarth

John Haygarth

John Haygarth was an important 18th-century British physician who discovered new ways to prevent the spread of fever among patients and reduce the mortality rate of smallpox....

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

Austin Flint murmur

In cardiology, an Austin Flint murmur is a mid-diastolic or presystolic murmur low-pitched rumbling murmur which is best heard at the cardiac apex...

(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 he terms "placebo" or "placeboic remedy" were used to refer to a dummy simulator in a clinical trial.

Flint treated 13 hospital inmates who had rheumatic fever

Rheumatic fever

Rheumatic fever is an inflammatory disease that occurs following a Streptococcus pyogenes infection, such as strep throat or scarlet fever. Believed to be caused by antibody cross-reactivity that can involve the heart, joints, skin, and brain, the illness typically develops two to three weeks after...

; 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 complication

Complication (medicine)

Complication, in medicine, is an unfavorable evolution of a disease, a health condition or a medical treatment. The disease can become worse in its severity or show a higher number of signs, symptoms or new pathological changes, become widespread throughout the body or affect other organ systems. A...

s. In the thirteenth case, Flint expressed some doubt as to whether the particular complications that had emerged (namely, pericarditis

Pericarditis

Pericarditis is an inflammation of the pericardium . A characteristic chest pain is often present.The causes of pericarditis are varied, including viral infections of the pericardium, idiopathic causes, uremic pericarditis, bacterial infections of the precardium Pericarditis is an inflammation of...

, endocarditis

Endocarditis

Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves . Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or even on intracardiac devices...

, and pneumonia

Pneumonia

Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...

) would have been prevented if that subject had been immediately given the "active treatment".

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

World War II

World War II, or the Second World War , was a global conflict lasting from 1939 to 1945, involving most of the world's nations—including all of the great powers—eventually forming two opposing military alliances: the Allies and the Axis...

1946, pharmaceutical chemicals were restricted, and one U.S. headache remedy manufacturer sold a drug composed of three ingredients: a, b, and c, and chemical b was in particular short supply.

Jellinek set up a complex trial involving 199 subjects, all of whom suffered from "frequent headaches". The subjects were randomly divided into four test groups. He prepared four test drugs, involving various permutation

Permutation

In mathematics, the notion of permutation is used with several slightly different meanings, all related to the act of permuting objects or values. Informally, a permutation of a set of objects is an arrangement of those objects into a particular order...

s of the three drug constituents, with a placebo as a scientific control

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". (Note that the trial conducted by Austin Flint is an example of such a drug efficacy vs. placebo efficacy trial.) The four test drugs were identical in shape, size, colour and taste:

Drug A: contained a, b, and c.
Drug B: contained a and c.
Drug C: contained a and b.
Drug D: a 'simulator', contained "ordinary lactate
Lactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...

".

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 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 for each of the four groups were:

A, B, C, D
B, A, D, C
C, D, A, B
D, C, B, A.

Over the entire population of 199 subjects, there were 120 "subjects reacting to placebo" and 79 "subjects not reacting to placebo".

On initial analysis, 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, further analysis on the trial demonstrated that ingredient b made a significant contribution to the remedy’s efficacy. Examining his data, 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.

Two conclusions came from this trial:

Jellinek, having identified 120 "placebo reactors", went on to suppose that all of them may have been suffering from either "psychological headaches" (with or without attendant "hypochondria
Hypochondria
Hypochondriasis or hypochondria refers to excessive preoccupation or worry about having a serious illness. This debilitating condition is the result of an inaccurate perception of the body’s condition despite the absence of an actual medication condition...

sis") or "true physiological headaches [which were] accessible to suggestion". Thus, according to this view, the degree to which a "placebo response" is present tends to be an index of the psychogenic
Psychosomatic illness
Psychosomatic medicine is an interdisciplinary medical field studying the relationships of social, psychological, and behavioral factors on bodily processes and well-being in humans and animals...

origins of the condition in question.
It indicated that, whilst any given placebo was inert, a responder to that particular placebo may be responding for a wide number of reasons unconnected with the drug's active ingredients; and, from this, it could be important to pre-screen
Screening (medicine)
Screening, in medicine, is a strategy used in a population to detect a disease in individuals without signs or symptoms of that disease. Unlike what generally happens in medicine, screening tests are performed on persons without any clinical sign of disease....

potential test populations, and treat those manifesting a placebo-response as a special group, or remove them altogether from the test population.

MRC and randomized trials

It used to be thought that the first-ever randomized clinical trial was the trial conducted by the Medical Research Council

Medical Research Council (UK)

The Medical Research Council is a publicly-funded agency responsible for co-ordinating and funding medical research in the United Kingdom. It is one of seven Research Councils in the UK and is answerable to, although politically independent from, the Department for Business, Innovation and Skills...

(MRC) in 1948 into the efficacy of streptomycin

Streptomycin

Streptomycin is an antibiotic drug, the first of a class of drugs called aminoglycosides to be discovered, and was the first antibiotic remedy for tuberculosis. It is derived from the actinobacterium Streptomyces griseus. Streptomycin is a bactericidal antibiotic. Streptomycin cannot be given...

in the treatment of pulmonary tuberculosis. In this trial, there were two test groups:

those "treated by streptomycin
Streptomycin
Streptomycin is an antibiotic drug, the first of a class of drugs called aminoglycosides to be discovered, and was the first antibiotic remedy for tuberculosis. It is derived from the actinobacterium Streptomyces griseus. Streptomycin is a bactericidal antibiotic. Streptomycin cannot be given...

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

What made this trial novel 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 could be biased

Bias of an estimator

In statistics, bias of an estimator is the difference between this estimator's expected value and the true value of the parameter being estimated. An estimator or decision rule with zero bias is called unbiased. Otherwise the estimator is said to be biased.In ordinary English, the term bias is...

, because those admitting each patient knew to which group that patient would be allocated (and so 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 they would occupy).

Recently, an earlier MRC trial on the antibiotic patulin on the course of common colds has been suggested to have been the first randomized trial. Another early and until recently overlooked randomized trial was published on strophanthin in a local Finnish journal in 1946.

Ethics

Bioethicists have raised diverse concerns on the use of placebos in modern medicine and research.

Disclosure. Rules that govern modern clinical trials insist on full disclosure to subjects who take part. Today, subjects are told that they may receive the drug being tested or they may receive the placebo.
Balancing Treatment vs. Research Objectives. Ethicists have also raised concerns on the use of placebos in those circumstances in which a standard treatment
Standard treatment
Standard treatment . The treatment that is normally provided to people with a given condition. In many studies, a control group receives the standard treatment while a treatment group receives the experimental treatment...

exists unless there are genuine doubts of the effectivity of such standard treatment. If standard treatments exist for the disease being studied in clinical trials, a standard treatment is always used in place of a placebo for serious diseases. In research experimental studies, the method of establishing a proper control group to eliminate the placebo effect has also been difficult, particularly for surgical and therapy interventions that are not pharmaceutical in nature. Notably, there has been much debate of whether to use a placebo pill or conduct a sham procedure as a control.

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

Declaration of Helsinki

From the time of the Hippocratic Oath

Hippocratic Oath

The Hippocratic Oath is an oath historically taken by physicians and other healthcare professionals swearing to practice medicine ethically. It is widely believed to have been written by Hippocrates, often regarded as the father of western medicine, or by one of his students. The oath is written in...

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
Nuremberg Code
The Nuremberg Code is a set of research ethics principles for human experimentation set as a result of the Subsequent Nuremberg Trials at the end of the Second World War.-Background:...

, which was issued in August 1947, as a consequence of the so-called Doctors' Trial

Doctors' Trial

The Doctors' Trial was the first of 12 trials for war crimes that the United States authorities held in their occupation zone in Nuremberg, Germany after the end of World War II. These trials were held before U.S...

which examined the human experimentation

Nazi human experimentation

Nazi human experimentation was a series of medical experiments on large numbers of prisoners by the Nazi German regime in its concentration camps mainly in the early 1940s, during World War II and the Holocaust. Prisoners were coerced into participating: they did not willingly volunteer and there...

conducted by Nazi

Nazism

Nazism, the common short form name of National Socialism was the ideology and practice of the Nazi Party and of Nazi Germany...

doctors during World War II

World War II

, offers ten principles for legitimate medical research, including informed consent

Informed consent

Informed consent is a phrase often used in law to indicate that the consent a person gives meets certain minimum standards. As a literal matter, in the absence of fraud, it is redundant. An informed consent can be said to have been given based upon a clear appreciation and understanding of the...

, absence of coercion

Coercion

Coercion is the practice of forcing another party to behave in an involuntary manner by use of threats or intimidation or some other form of pressure or force. In law, coercion is codified as the duress crime. Such actions are used as leverage, to force the victim to act in the desired way...

, and beneficence

Beneficence

Beneficence is a bronze statue on the campus of Ball State University, located in Muncie, Indiana. It is referred to as "Benny" by the students.-History:...

towards experiment participants.

In 1964, the World Medical Association

World Medical Association

The World Medical Association is an international and independent confederation of free professional Medical Associations, therefore representing physicians worldwide...

issued the Declaration of Helsinki
Declaration of Helsinki
The Declaration of Helsinki is a set of ethical principles regarding human experimentation developed for the medical community by the World Medical Association . It is widely regarded as the cornerstone document of human research ethics...

,http://www.wma.net/e/policy/b3.htm 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.

External links

James Lind Library A source of historical texts on fair tests of treatments in health care.

The source of this article is wikipedia, the free encyclopedia. The text of this article is licensed under the GFDL.

Overview

Blind trials

Double-blind trials

Natural history groups

Indexing

Placebo ingredients

Adherence

Placebo recognition

James Lind and scurvy

Animal magnetism

Perkins tractors

Flint and placebo active treatment comparison

Jellinek and headache remedy ingredients

MRC and randomized trials

Ethics

Declaration of Helsinki

See also

External links