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For other uses, see Placebo (disambiguation) and Placebo effect (disambiguation).
Placebos are typically inert tablets, such as sugar pills

A placebo is a substance or treatment with no active therapeutic effect.[1] Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery,[2] and other procedures.[3]

In drug testing and medical research, a placebo can be made to resemble an active medication or therapy so that it functions as a control; this is to prevent the recipient(s) and/or others from knowing (with their consent) whether a treatment is active or inactive, as expectations about efficacy can influence results.[4][5] In a clinical trial any change in the placebo arm is known as the placebo response, and the difference between this and the result of no treatment is the placebo effect.[6]

A placebo may be given to a person in a clinical context in order to deceive the recipient into thinking that it is an active treatment. The use of placebos as treatment in clinical medicine is ethically problematic as it introduces deception and dishonesty into the doctor–patient relationship.[7] Placebos have no impact on disease itself; at most they affect peoples' assessment of their own condition.[8]

Historically, an influential 1955 study entitled The Powerful Placebo established the idea that placebo effects were clinically important,[9] and were a result of the brain's role in physical health, but a 1997 review of the study found "no evidence [...] of any placebo effect in any of the studies cited".[10] The placebo effect is certainly a pervasive idea;[11] in fact, it is part of the recorded response to any active medical intervention.[12] However, research has found placebo interventions result in no important effect on clinical outcomes in general, and only in certain settings (especially for pain and nausea) they can influence patient-reported outcomes, though it is difficult to distinguish true placebo effects from biased reporting by the patient.[13][9]

Types

Common placebos include pills ("sugar pills") or saline injections. Fake surgeries have also seen some use. An example is the Finnish Meniscal Legion Study Group’s trial published in The New England Journal of Medicine, which found a sham meniscal surgery to be equally effective to the actual procedure.[14][15]

Non-inert 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 affected the results. For example, one study on cholesterol-lowering drugs used olive oil and corn oil 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. The placebo that was used included lactose. However, since cancer patients typically face a higher risk of lactose intolerance, the placebo pill might actually have caused unintended side-effects that made the experimental drug look better in comparison.[16]

Definitions

In a 1983 article largely attributing the observed results to statistical regression, Clement J. McDonald and others defined a placebo as "a substance or procedure... that is objectively without specific activity for the condition being treated".[17]

In a clinical trial, a placebo response is the measured response of subjects to a placebo; the placebo effect is the difference between that response, and no treatment.[6]

Effects

Placebos have no meaningful therapeutic worth.[13] They have no effect on disease, but at most only affect some people's subjective judgement of their symptoms.[8] Sometimes they can make people feel better, and sometimes worse – in which case they are termed a nocebo.[8]

Because the placebo response is simply the patient response that cannot be attributed to an investigational intervention, there are multiple possible components of a measured placebo effect. These components have varying relevance depending on study design and the types of observations.[10] While there is some evidence that placebo interventions can alter levels of endocannabinoids[18] or endogenous opioids,[19] other prominent components include expectancy effects, regression to the mean,[17][20] and flawed research methodologies.[21]

Objective and subjective effects

Expectation plays a clear role. A placebo presented as a stimulant may trigger an effect on heart rhythm and blood pressure, but when administered as a depressant, the opposite effect.[22]

Brain imaging techniques done by Emeran Mayer, Johanna Jarco and Matt Lieberman showed some physiological changes in the brain.[23] Placebos can produce some objective physiological changes, such as changes in heart rate, blood pressure, and chemical activity in the brain, in cases involving pain, depression, anxiety, fatigue, and some symptoms of Parkinson’s. However, in other cases, like asthma, the effect is purely subjective, when the patient reports improvement despite no objective change in the underlying condition.[23][24] One explanation of the reported improvement is, in the words of Mike Hall, that "patients [are] telling doctors what they want to hear". If this is indeed the case, it casts doubt on a larger body of placebo research, which generally finds placebo effects in self-reported outcomes. [25]

Factors influencing the power of the placebo effect

A review published in JAMA Psychiatry found that, in trials of antipsychotic medications, the change in response to receiving a placebo had increased significantly between 1960 and 2013. The review's authors identified several factors that could be responsible for this change, including inflation of baseline scores and enrollment of fewer severely ill patients.[26] Another analysis published in Pain in 2015 found that placebo responses had increased considerably in neuropathic pain clinical trials conducted in the United States from 1990 to 2013. The researchers suggested that this may be because such trials have "increased in study size and length" during this time period.[27]

Ethics

See also: Medical ethics and Philosophy of medicine

In research trials

Knowingly giving a person a placebo when there is an effective treatment available is a bioethically complex issue. While placebo-controlled trials might provide information about the effectiveness of a treatment, it denies some patients what could be the best available (if unproven) treatment. Informed consent is usually required for a study to be considered ethical, including the disclosure that some test subjects will receive placebo treatments.

The ethics of placebo-controlled studies have been debated in the revision process of the Declaration of Helsinki.[28] Of particular concern has been the difference between trials comparing inert placebos with experimental treatments, versus comparing the best available treatment with an experimental treatment; and differences between trials in the sponsor's developed countries versus the trial's targeted developing countries.[29]

Some suggest that existing medical treatments should be used instead of placebos, to avoid having some patients not receive medicine during the trial.[30]

In medical practice

A study of Danish general practitioners found that 48% had prescribed a placebo at least 10 times in the past year.[11] The most frequently prescribed placebos were presented as antibiotics for viral infections, and vitamins for fatigue. Specialists and hospital-based physicians reported much lower rates of placebo use. A 2004 study in the British Medical Journal of physicians in Israel found that 60% used placebos in their medical practice, most commonly to "fend off" requests for unjustified medications or to calm a patient.[31] The accompanying editorial concluded, "We cannot afford to dispense with any treatment that works, even if we are not certain how it does."[32] Other researchers have argued that open provision of placebos for treating ADHD in children can be effective in maintaining ADHD children on lower stimulant doses in the short term.[33]

Critics of the practice responded that it is unethical to prescribe treatments that do not work, and that telling a patient (as opposed to a research test subject) that a placebo is a real medication is deceptive and harms the doctor–patient relationship in the long run. Critics also argued that using placebos can delay the proper diagnosis and treatment of serious medical conditions.[34] While some say that blanket consent, or the general consent to unspecified treatment given by patients beforehand, is ethical, others argue that patients should always obtain specific information about the name of the drug they are receiving, its side effects, and other treatment options.[35] This view is shared by some on the grounds of patient autonomy.[36] There are also concerns that legitimate doctors and pharmacists could open themselves up to charges of fraud or malpractice by using a placebo.[37]

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.[32] 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."

Referring specifically to homeopathy, the House of Commons of the United Kingdom Science and Technology Committee has stated:

In the Committee's view, homeopathy is a placebo treatment and the Government should have a policy on prescribing placebos. The Government is reluctant to address the appropriateness and ethics of prescribing placebos to patients, which usually relies on some degree of patient deception. Prescribing of placebos is not consistent with informed patient choice—which the Government claims is very important—as it means patients do not have all the information needed to make choice meaningful. Beyond ethical issues and the integrity of the doctor–patient relationship, prescribing pure placebos is bad medicine. Their effect is unreliable and unpredictable and cannot form the sole basis of any treatment on the NHS.[38]

A survey in the United States of more than 10,000 physicians came to the result that while 24% of physicians would prescribe a treatment that is a placebo simply because the patient wanted treatment, 58% would not, and for the remaining 18%, it would depend on the circumstances.[39]

Mechanisms

Studies of the "placebo effect" often fail to adequately identify confounding factors.[40] False impressions of placebo effects are caused by many factors including:[10][41][40]

  • Natural course of the diseases including spontaneous improvement, fluctuation of symptoms;
  • Regression to the mean;
  • Additional treatments
  • conditional switching of placebo treatment
  • Biases, including scaling bias, answers of politeness, experimental subordination, conditioned answers;
  • Experimenter and observer biases including misjudgment or irrelevant response variables;
  • Psychological effects including psychosomatic phenomena, expectation effects and classical conditioning.

Psychology

The "placebo effect" may be related to expectations

In psychology, the two main hypotheses of placebo effect are expectancy theory and classical conditioning.[41]

In 1985, Irving Kirsch hypothesized that placebo effects are produced by the self-fulfilling effects of response expectancies, in which the belief that one will feel different leads a person to actually feel different.[42] According to this theory, the belief that one has received an active treatment can produce the subjective changes thought to be produced by the real treatment. Placebos can act similarly through classical conditioning, wherein a placebo and an actual stimulus are used simultaneously until the placebo is associated with the effect from the actual stimulus.[43] Both conditioning and expectations play a role in placebo effect,[41] and make different kinds of contribution. Conditioning has a longer-lasting effect,[44] and can affect earlier stages of information processing.[45] Those that think that a treatment will work display a stronger placebo effect than those that do not, as evidenced by a study of acupuncture.[46][47]

Additionally, motivation may contribute to the placebo effect. The active goals of an individual changes their somatic experience by altering the detection and interpretation of expectation-congruent symptoms, and by changing the behavioral strategies a person pursues.[48][49] Motivation may link to the meaning through which people experience illness and treatment. Such meaning is derived from the culture in which they live and which informs them about the nature of illness and how it responds to treatment.

Placebo effect and the brain

Functional imaging upon placebo analgesia suggests links to the activation, and increased functional correlation between this activation, in the anterior cingulate, prefrontal, orbitofrontal and insular cortices, nucleus accumbens, amygdala, the brainstem periaqueductal gray matter,[50][51][52] and the spinal cord.[53][54][55][56]

The higher brain works by regulating subcortical processes. High placebo responses link with enhanced dopamine and mu-opioid activity in the circuitry for reward responses and motivated behavior of the nucleus accumbens, and, on the converse, anti-analgesic nocebos responses were associated with deactivation in this part of the brain of dopamine and opioid release.[51] (It has been known that placebo analgesia depends upon the release in the brain of endogenous opioids since 1978.[57]) Such analgesic placebos activation changes processing lower down in the brain by enhancing the descending inhibition through the periaqueductal gray[51] on spinal nociceptive reflexes, while the expectations of anti-analgesic nocebos acts in the opposite way to block this.[53]

Functional imaging upon placebo analgesia has been summarized as showing that the placebo response is "mediated by "top-down" processes dependent on frontal cortical areas that generate and maintain cognitive expectancies. Dopaminergic reward pathways may underlie these expectancies".[58] "Diseases lacking major 'top-down' or cortically based regulation may be less prone to placebo-related improvement".[59]

Brain and body

Further information: Neural top–down control of physiology

The brain has control over the body processes affected by placebos.

In conditioning, a neutral stimulus saccharin is paired in a drink with an agent that produces an unconditioned response. For example, that agent might be cyclophosphamide, which causes immunosuppression. After learning this pairing, the taste of saccharin by itself is able to cause immunosuppression, as a new conditioned response via neural top-down control.[60] Such conditioning has been found to affect a diverse variety of not just basic physiological processes in the immune system but ones such as serum iron levels, oxidative DNA damage levels, and insulin secretion. Recent reviews have argued that the placebo effect is due to top-down control by the brain for immunity[61] and pain.[62] Pacheco-López and colleagues have raised the possibility of "neocortical-sympathetic-immune axis providing neuroanatomical substrates that might explain the link between placebo/conditioned and placebo/expectation responses."[61]: 441  There has also been research aiming to understand underlying neurobiological mechanisms of action in pain relief, immunosuppression, Parkinson's disease and depression.[63]

Dopaminergic pathways have been implicated in the placebo response in pain and depression.[64]

Negative effects

See also: Nocebo

A phenomenon opposite to the placebo effect has also been observed. When an inactive substance or treatment is administered to a recipient who has an expectation of it having a negative impact, this intervention is known as a nocebo (Latin nocebo = "I shall harm").[65] A nocebo effect occurs when the recipient of an inert substance reports a negative effect and/or a worsening of symptoms, with the outcome resulting not from the substance itself, but from negative expectations about the treatment.[66][67]

Another negative consequence is that placebos can cause side-effects associated with real treatment.[68] One example of this is with those that have already taken an opiate, can then show respiratory depression when given it again in the form of a placebo.[69]

Withdrawal symptoms can also occur after placebo treatment. This was found, for example, after the discontinuation of the Women's Health Initiative study of hormone replacement therapy for menopause. Women had been on placebo for an average of 5.7 years. Moderate or severe withdrawal symptoms were reported by 4.8% of those on placebo compared to 21.3% of those on hormone replacement.[70]

Symptoms and conditions

A 2010 Cochrane review suggests that placebo effects are only apparent in subjective, continuous measures, and in the treatment of pain and related conditions.[13]

Pain

The placebo effect is believed to reduce pain—a phenomenon known as placebo analgesia—in two different ways. One way is by the placebo initiating the release of endorphins, which are natural pain killers produced by the brain.[71] The other way is the placebo changing the patient's perception of pain. "A person might reinterpret a sharp pain as uncomfortable tingling."[8]

One way in which the magnitude of placebo analgesia can be measured is by conducting "open/hidden" studies, in which some patients receive an analgesic and are informed that they will be receiving it (open), while others are administered the same drug without their knowledge (hidden). Such studies have found that analgesics are considerably more effective when the patient knows they are receiving them.[72]

Depression

In 2008, a controversial meta-analysis led by psychologist Irving Kirsch, analyzing data from the FDA, concluded that 82% of the response to antidepressants was accounted for by placebos.[73] However, there are serious doubts about the used methods and the interpretation of the results, especially the use of 0.5 as cut-off point for the effect-size.[74] A complete reanalysis and recalculation based on the same FDA data discovered that the Kirsch study suffered from important flaws in the calculations. The authors concluded that although a large percentage of the placebo response was due to expectancy, this was not true for the active drug. Besides confirming drug effectiveness, they found that the drug effect was not related to depression severity.[75]

Another meta-analysis found that 79% of depressed patients receiving placebo remained well (for 12 weeks after an initial 6–8 weeks of successful therapy) compared to 93% of those receiving antidepressants. In the continuation phase however, patients on placebo relapsed significantly more often than patients on antidepressants.[76] A 2009 meta-analysis reported that in 2005 68% of the effects of antidepressants was due to the placebo effect, which was more than double the placebo response rate in 1980.[77]

Chronic fatigue syndrome

It was previously assumed that placebo response rates in patients with chronic fatigue syndrome (CFS) are unusually high, "at least 30% to 50%", because of the subjective reporting of symptoms and the fluctuating nature of the condition. According to a meta-analysis and contrary to conventional wisdom, the pooled response rate in the placebo group was 19.6%, even lower than in some other medical conditions. The authors offer possible explanations for this result: CFS is widely understood to be difficult to treat, which could reduce expectations of improvement. In context of evidence showing placebos do not have powerful clinical effects when compared to no treatment, a low rate of spontaneous remission in CFS could contribute to reduced improvement rates in the placebo group. Intervention type also contributed to the heterogeneity of the response. Low patient and provider expectations regarding psychological treatment may explain particularly low placebo responses to psychiatric treatments.[78]

History

Main article: Placebo in history
A quack treating a patient with Perkins Patent Tractors by James Gillray, 1801. John Haygarth used this remedy to illustrate the power of the placebo effect.

The word 'placebo', Latin for "I will please", dates back to a Latin translation of the Bible by St Jerome.[79] In 1811, Hooper’s Quincy’s Lexicon-Medicum defined placebo as "[any medicine] adapted more to please than to benefit the patient".[80][81]

Early implementations of placebo controls date back to 16th-century Europe with Catholic efforts to discredit exorcisms. Individuals who claimed to be possessed by demonic forces were given false holy objects. If the person reacted with violent contortions, it was concluded that the possession was purely imagination.[82]

Use of the placebo effect as a medical treatment has been controversial throughout history, and was common until the mid twentieth century.[83] In 1903 Richard Cabot concluded that it should be avoided because it is deceptive. Newman points out the "placebo paradox" – it may be unethical to use a placebo, but also unethical "not to use something that heals". He suggests to solve this dilemma by appropriating the meaning response in medicine, that is make use of the placebo effect, as long as the "one administering... is honest, open, and believes in its potential healing power".[7]

John Haygarth was the first to investigate the efficacy of the placebo effect in the 18th century.[84] He tested a popular medical treatment of his time, called "Perkins tractors", and concluded that the remedy was ineffectual by demonstrating that the results from a dummy remedy were just as useful as from the alleged "active" remedy.[85]

Émile Coué, a French pharmacist, working as an apothecary at Troyes between 1882 and 1910, also advocated the effectiveness of the "Placebo Effect". He became known for reassuring his clients by praising each remedy's efficiency and leaving a small positive notice with each given medication. His book Self-Mastery Through Conscious Autosuggestion was published in England (1920) and in the United States (1922).

Placebos remained widespread in medicine until the 20th century, and they were sometimes endorsed as necessary deceptions.[83] In 1903, Richard Cabot said that he was brought up to use placebos,[83] but he ultimately concluded by saying that "I have not yet found any case in which a lie does not do more harm than good".[7]

T. C. Graves first defined the "placebo effect" in a published paper in The Lancet in 1920.[original research?][86] He spoke of "the placebo effects of drugs" being manifested in those cases where "a real psychotherapeutic effect appears to have been produced".[87]

Henry K. Beecher, in a paper in 1955,[9] suggested placebo effects occurred in about 35% of people. However, this paper has been criticized for failing to distinguish the placebo effect from other factors, and for thereby encouraging an inflated notion of the placebo effect,[88] and a 1997 re-analysis failed to support Beecher's conclusions.[10]

In 1955, Henry K. Beecher published the classic work entitled ‘‘The Powerful Placebo.’’ Since that time, 40 years ago, the placebo effect has been considered a scientific fact. Beecher was the first scientist to quantify the placebo effect. [...] This publication is still the most frequently cited placebo reference. Recently Beecher’s article was reanalyzed with surprising results: In contrast to his claim, no evidence was found of any placebo effect in any of the studies cited by him.

— Kienle & Kiene, The Powerful Placebo Effect: Fact or Fiction? [10]

In 1961 Henry K. Beecher concluded that surgeons he categorized as enthusiasts relieved their patients' chest pain and heart problems more than skeptic surgeons.[7] Beginning in the 1960s, the placebo effect became widely recognized and placebo-controlled trials became the norm in the approval of new medications.[89]

Dylan Evans argues that placebos are linked with activation of the acute-phase response so will work only on subjective conditions such as pain, swelling, stomach ulcers, depression, and anxiety that are linked to this.[90]

A 2001 systematic review of clinical trials concluded that there was no evidence of clinically important effects, except perhaps in the treatment of pain and continuous subjective outcomes.[9] The authors later published a Cochrane review with similar conclusions (updated as of 2010).[13] Most studies have attributed the difference from baseline until the end of the trial to a placebo effect, but the reviewers examined studies which had both placebo and untreated groups in order to distinguish the placebo effect from the natural progression of the disease.[9]

Placebo observations differ between individuals.[91][92] In the 1950s, there was considerable research to find whether there was a specific personality to those that responded to placebos. The findings could not be replicated[93] and it is now thought to have no effect.[94]

The desire for relief from pain, "goal motivation", and how far pain is expected to be relieved increases placebo analgesia.[48] Another factor increasing the effectiveness of placebos is the degree to which a person attends to their symptoms, "somatic focus".[49] Individual variation in response to analgesic placebos has been linked to regional neurochemical differences in the internal affective state of the individuals experiencing pain.[95]

Children seem to have greater response than adults to placebos.[96]

Placebo-controlled studies

Main article: Placebo-controlled study

The placebo effect makes it more difficult to evaluate new treatments. Clinical trials control for this effect by including a group of subjects that receives a sham treatment. The subjects in such trials are blinded as to whether they receive the treatment or a placebo. If a person is given a placebo under one name, and they respond, they will respond in the same way on a later occasion to that placebo under that name but not if under another.[97]

Clinical trials are often double-blinded so that the researchers also do not know which test subjects are receiving the active or placebo treatment. The placebo effect in such clinical trials is weaker than in normal therapy since the subjects are not sure whether the treatment they are receiving is active.[98]

Pronunciation and etymology

Placebo is pronounced /pləˈsiːboʊ/ plə-SEE-boh. It is from Latin placēbō, "I shall please"[99] from placeō, "I please")[100][101]

See also

References

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