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Placebos are typically inert tablets, such as sugar pills

A placebo (/pləˈsb/ plə-SEE-boh) is a substance or treatment of no intended therapeutic value.[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) 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; they can only affect the person’s perception 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] Subsequent research has found that placebos are not a useful means of therapy.[11]

The word “placebo”, Latin for “I will please”, dates back to a Latin translation of the Bible by St Jerome.[12]

The American Society of Pain Management Nursing define a placebo as “any sham medication or procedure designed to be void of any known therapeutic value”.[1]

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] It is also part of the recorded response to any active medical intervention.[13]

Any measurable placebo effect is termed either objective (e.g. lowered blood pressure) or subjective (e.g. a lowered perception of pain).[1]

Placebos have no meaningful therapeutic worth.[11] They have no effect on disease, and can 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[14] or endogenous opioids,[15] other prominent components include expectancy effects, regression to the mean,[16][17] and flawed research methodologies.[18]

Children seem to have greater response than adults to placebos.[19]

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.[20] 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.[21]

A 2010 Cochrane review suggests that placebo effects are only apparent in subjective, continuous measures, and in the treatment of pain and related conditions.[11]

Placebos are believed to be capable of altering a person’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.[22]

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.[23] 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.[24] 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.[25]

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.[26]

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.[27]

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”).[28] A nocebo effect occurs when the recipient of an inert substance reports a negative effect or a worsening of symptoms, with the outcome resulting not from the substance itself, but from negative expectations about the treatment.[29][30]

Another negative consequence is that placebos can cause side-effects associated with real treatment.[31]

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.[32]

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.[33] 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.[34]

Some suggest that existing medical treatments should be used instead of placebos, to avoid having some patients not receive medicine during the trial.[35]

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.[36] 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.[37]This view is shared by some on the grounds of patient autonomy.[38] There are also concerns that legitimate doctors and pharmacists could open themselves up to charges of fraud or malpractice by using a placebo.[39]

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.[40] 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:

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.[42]

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.[43]

The “placebo effect” may be related to expectations

In psychology, the two main hypotheses of placebo effect are expectancy theory and classical conditioning.[44]

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.[45] 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.[46] Both conditioning and expectations play a role in placebo effect,[44] and make different kinds of contribution. Conditioning has a longer-lasting effect,[47] and can affect earlier stages of information processing.[48] 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.[49]

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.[50] 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.

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,[51][52] and the spinal cord.[53][54][55]

It has been known that placebo analgesia depends upon the release in the brain of endogenous opioids since 1978.[56] Such analgesic placebos activation changes processing lower down in the brain by enhancing the descending inhibition through the periaqueductal gray 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”.[57] “Diseases lacking major ‘top-down’ or cortically based regulation may be less prone to placebo-related improvement”.[58]

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.[59] 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[60] and pain.[61] 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.”[60]:441 There has also been research aiming to understand underlying neurobiological mechanisms of action in pain relief, immunosuppression, Parkinson’s disease and depression.[15]

Dopaminergic pathways have been implicated in the placebo response in pain and depression.[62]

Placebo-controlled studies, as well as studies of the placebo effect itself, often fail to adequately identify confounding factors.[8][63][64] False impressions of placebo effects are caused by many factors including:[8][10][64][44][63]

  • Regression to the mean (natural recovery or fluctuation of symptoms)
  • Additional treatments
  • Response bias from subjects, including scaling bias, answers of politeness, experimental subordination, conditioned answers;
  • Reporting bias from experimenters, including misjudgment and irrelevant response variables.
  • Non-inert ingredients of the placebo medication having an unintended physical effect

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 was used in a medicinal context in the late 18th century to describe a “commonplace method or medicine” and in 1811 it was defined as “any medicine adapted more to please than to benefit the patient”. Although this definition contained a derogatory implication[65] it did not necessarily imply that the remedy had no effect.[66]

Placebos have featured in medical use until well into the twentieth century.[67] In 1955 Henry K. Beecher published an influential paper entitled The Powerful Placebo which proposed idea that placebo effects were clinically important.[9] Subsequent re-analysis of his materials, however, found in them no evidence of any “placebo effect”.[10]

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.[68]

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.[69]

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