Placebo
Encyclopedia
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient. Sometimes patients given a placebo treatment will have a perceived or actual improvement in a medical condition, a phenomenon commonly called the placebo effect.
In medical research, placebos are given as control
treatments and depend on the use of measured deception. Common placebos are inert tablets, sham surgery
, and other procedures based on false information. However, placebos can also have a surprisingly positive effect on a patient who knows that the given treatment is without any active drug, as compared with a control group who knowingly did not get a placebo.
In one common placebo procedure, however, a patient is given an inert pill, told that it may improve his/her condition, but not told that it is in fact inert. Such an intervention may cause the patient to believe the treatment will change his/her condition; and this belief may produce a subjective perception of a therapeutic effect
, causing the patient to feel their condition has improved — or an actual improvement in their condition. This phenomenon is known as the placebo effect.
Placebos are widely used in medical research and medicine
, and the placebo effect is a pervasive phenomenon; in fact, it is part of the response to any active medical intervention. Archie Cochrane suggested in 1972 "It is important to distinguish the very respectable, conscious use of placebos. The effect of placebos has been shown by randomised controlled trials to be very large. Their use in the correct place is to be encouraged […]"
The placebo effect points to the importance of perception and the brain's role in physical health
. However, when used as treatment in clinical medicine (as opposed to laboratory research), the deception involved in the use of placebos creates tension between the Hippocratic Oath
and the honesty of the doctor-patient relationship. The United Kingdom Parliamentary Committee on Science and Technology has stated that: "...prescribing placebos... usually relies on some degree of patient deception" and "prescribing pure placebos is bad medicine. Their effect is unreliable and unpredictable and cannot form the sole basis of any treatment on the NHS."
Since the publication of Henry K. Beecher
's The Powerful Placebo in 1955, the phenomenon has been considered to have clinically important effects. This view was notably challenged when, in 2001, a 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. The article received a flurry of criticism, but the authors later published a Cochrane
review with similar conclusions (updated ). Most studies have attributed the difference from baseline till 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. However these conclusions have been criticized because of the great variety of diseases—more than 40—in this metastudy. The effect of placebo is very different in different diseases. By pooling quite different diseases the results can be levelled out.
substances administered
through any means can act as placebos, including pills
, creams
, inhalants
, and injections
. Medical devices such as ultrasound
can act as placebos. Sham surgery
, sham electrodes implanted in the brain
, and sham acupuncture, either with sham needles or on fake acupuncture points, have all exhibited placebo effects. Bedding not treated to reduce allergies has been used as a placebo to control for treated bedding. The physician
has even been called a placebo;33–34 a study found that patient recovery can be increased by words that suggest the patient “would be better in a few days”, and if the patient is given treatment, that “the treatment would certainly make him better” rather than negative words such as “I am not sure that the treatment I am going to give you will have an effect”. The placebo effect may be a component of pharmacological therapies: Pain killing
and anxiety reducing drugs
that are infused secretly without an individual’s knowledge are less effective than when a patient knows they are receiving them. Likewise, the effects of stimulation from implanted electrodes in the brains of those with advanced Parkinson's disease
are greater when they are aware they are receiving this stimulation. Sometimes administering or prescribing a placebo merges into fake medicine.
The placebo effect has sometimes been defined as a physiological effect caused by the placebo, but Moerman and Jonas have pointed out that this seems illogical, as a placebo is an inert substance that does not directly cause anything. Instead they introduced the word "meaning response" for the meaning that the brain associates with the placebo, which causes a physiological placebo effect. They propose that the placebo, which may be unethical, could be avoided entirely if doctors comfort and encourage their patients' health. Ernst and Resch also attempted to distinguish between the "true" and "perceived" placebo effect, as they argued that some of the effects attributed to the placebo effect could be due to other factors.
The placebo effect has been controversial throughout history. Notable medical organizations have endorsed it, but 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". Another possible resolution of the ethical dilemma might come from the "honest placebo" effect found in a 2010 study carried out by researchers in the Program in Placebo Studies
at the Harvard Medical School
, where patients with irritable bowel syndrome experienced a significant beneficial effect even though they were told the pills they were taking were placebos, as compared to a control group who received no pills.
. It was first used in a medicinal context in the 18th century. In 1785 it was defined as a "commonplace method or medicine" and in 1811 it was defined as "any medicine adapted more to please than to benefit the patient", sometimes with a derogatory implication but not with the implication of no effect. Placebos were widespread in medicine until the 20th century, and they were sometimes endorsed as necessary deceptions. In 1903 Richard Cabot
said that he was brought up to use placebos, 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". In 1961 Henry K. Beecher
found that surgeons he categorized as enthusiasts relieved their patients' chest pain and heart problems more than skeptic surgeons. In 1961 Walter Kennedy introduced the word nocebo
. Beginning in the 1960s, the placebo effect became widely recognized and placebo controlled trials became the norm in the approval of new medications. Later, researchers became interested in understanding the placebo effect, rather than just controlling for its effects, and in 2011, a Program in Placebo Studies
was established at the Harvard Medical School
.
effect. The basic mechanisms of placebo effects have been investigated since 1978, when it was found that the opioid antagonist naloxone
could block placebo painkillers, suggesting that endogenous opioids are involved.
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. 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. Both conditioning and expectations play a role in placebo effect, and make different kinds of contribution. Conditioning has a longer-lasting effect, and can affect earlier stages of information processing. The expectancy effect can be enhanced through factors such as the enthusiasm of the doctor, differences in size and color of placebo pills, or the use of other interventions such as injections. In one study, the response to a placebo increased from 44% to 62% when the doctor treated them with "warmth, attention, and confidence". Expectancy effects have been found to occur with a range of substances. 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.
Because the placebo effect is based upon expectations and conditioning, the effect disappears if the patient is told that their expectations are unrealistic, or that the placebo intervention is ineffective. A conditioned pain reduction can be totally removed when its existence is explained. It has also been reported of subjects given placebos in a trial of anti-depressants, that "Once the trial was over and the patients who had been given placebos were told as much, they quickly deteriorated."
A placebo described as a muscle relaxant
will cause muscle relaxation and, if described as the opposite, muscle tension. A placebo presented as a stimulant
will have this effect on heart rhythm
, and blood pressure
, but, when administered as a depressant
, the opposite effect. The perceived consumption of caffeine has been reported to cause similar effects even when decaffeinated coffee is consumed, although a 2003 study found only limited support for this. Alcohol placebos can cause intoxication and sensorimotor impairment. Perceived ergogenic aids can increase endurance, speed and weight-lifting ability, leading to the question of whether placebos should be allowed in sport competition. Placebos can help smokers quit. Perceived allergens that are not truly allergenic can cause allergies. Interventions such as psychotherapy can have placebo effects.pp 164–173 The effect has been observed in the transplantation of human embryonic neurons into the brains of those with advanced Parkinson's disease
.
Because placebos are dependent upon perception and expectation, various factors that change the perception can increase the magnitude of the placebo response. For example, studies have found that the color and size of the placebo pill makes a difference, with "hot-colored" pills working better as stimulants while "cool-colored" pills work better as depressants. Capsules rather than tablet
s seem to be more effective, and size can make a difference. One researcher has found that big pills increase the effect while another has argued that the effect is dependent upon cultural background. More pills, branding, past experience, and high price increase the effect of placebo pills. Injection and acupuncture
have larger effect than pills. Proper adherence to placebos is associated with decreased mortality.
Motivation
may contribute to the placebo effect. The active goals of an individual changes his/her somatic experience by altering the detection and interpretation of expectation-congruent symptoms, and by changing the behavioral strategies a person pursues. 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. Research upon the placebo treatment of gastric and duodenal ulcers shows that this varies widely with society: those in Germany having a high-rate placebo effect while those in Brazil a low one. Placebo effects in treating gastric ulcers is low in Brazil, higher in northern Europe (Denmark, Netherlands), and extremely high in Germany. But the placebo effect for hypertension is lower in Germany than elsewhere Social observation can induce a placebo effect such when a person sees another having reduced pain following what they believe is a pain reducing procedure.
The placebo effect can work selectively. If an analgesic placebo cream is applied on one hand, it will reduce pain only in that hand and not elsewhere on the body 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.
upon placebo analgesia shows that it 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, and the spinal cord
.
These changes can act upon the brain’s early stages of information processing: Research using evoked brain potentials
upon painful laser pulses, for example, finds placebo effects upon the N2–P2, a biphasic negative–positive complex response, the N2 peak of which is at about 230 ms, and the P2 one at about 380 ms. They occur not only during placebo analgesia but after receiving the analgesic placebo (the areas are different here, and involve the medial prefrontal cortex, posterior parietal cortex
and inferior parietal lobule).
Different areas in the higher brain have different functions. The prefrontal involvement could be related to recalling the placebo and maintaining its cognitive presence in a "self-reinforcing feedback loop" (during pain an individual recalls having taken the placebo and reduced pain reinforces its status as an analgesic). The rostral anterior cingulate cortex (rACC) and its subcortical connectivity could be related to the expectation of potential pain stimuli
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. (It has been known that placebo analgesia depends upon the release in the brain of endogenous opioids since 1978.) 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.
The brain is also involved in less-studied ways upon nonanalgesic placebo effects:
Present 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". "Diseases lacking major 'top-down' or cortically based regulation may be less prone to placebo-related improvement".
, and fever
are directly organized by the brain. Other processes usually regulated by the body such as the immune system
are also controlled indirectly through the sympathetic and parasympathetic nervous system.
Research upon conditioning
in animals shows the brain can learn control over them. 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
that causes immunosuppression. After learning this pairing, the taste of saccharin by itself through neural top-down control created immunosuppression, as a new conditioned response. 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. This work was originally done on rats, however the same conditioning of basic physiological processes can also occur in humans. Recent reviews have argued the placebo effect is due to top-down control by the brain for immunity and pain. 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."pp 441
A recent fMRI study has shown that a placebo can reduce pain-related neural activity in the spinal cord, indicating that placebo effects can extend beyond the brain.
identifies many symptoms such as fever
, pain
, and sickness behavior
as evolved responses to protect or enhance the recovery from infection
and injury
. Fever
, for example, is an evolved self-treatment that removes bacteria
or viruses through raised body temperature
. These evolved
responses, however, also have a cost
that depending upon circumstances can outweigh their benefit (due to this, for example, there is a reduction in fever during malnutrition
or late pregnancy
). According to the health management system
theory proposed by Nicholas Humphrey
, the brain has been selected to ensure that evolved responses are deployed only when the cost benefit
is biologically advantageous. To do this, the brain factors in a variety of information sources, including the likelihood derived from beliefs that the body will get well without deploying its costly evolved responses. One such source of information is the knowledge the body is receiving care and treatment. The placebo effect in this perspective arises when false information about medications misleads the health management system about the likelihood of getting well so that it selects not to deploy an evolved self-treatment.
,
6 months for angina pectoris, and two and half years for rheumatoid arthritis
. Placebo effects after verbal suggestion for mild pain can be robust and still exist after being repeated ten times even if they have no actual pharmacological pain killing action.
. They found that in studies with a binary outcome, meaning patients were classified as improved or not improved, the placebo group had no statistically significant improvement over the no-treatment group. Likewise, there was no significant placebo effect in studies in which objective
outcomes (such as blood pressure) were measured by an independent observer. The placebo effect could be documented only in studies in which the outcomes (improvement or failure to improve) were reported by the subjects themselves. The authors concluded that the placebo effect does not have "powerful clinical effects," (objective effects) and that patient-reported improvements (subjective effects) in pain were small and could not be clearly distinguished from reporting bias
. Other researchers (Wampold et al.) re-analysed the same data from the 2001 meta-analysis and concluded that the placebo effects for objective symptom measures are comparable to placebo effects for subjective ones and that the placebo effect can exceed the effect of the active treatment by 20% for disorders amenable to the placebo effect, a conclusion which Hróbjartsson & Gøtzsche described as "powerful spin". Another group of researchers noted the dramatically different conclusions between these two sets of authors despite nearly identical meta-analytic results, and suggested that placebo effects are indeed significant but small in magnitude.
Hróbjartsson and Gøtzsche's conclusion has been criticised on several grounds. Their meta-analysis covered studies into a highly mixed group of conditions: The placebo effect does occur with peripheral disease processes (such as hypertension, asthma, prostatic hyperplasia, anal fissure, bronchitis), though not for processes reflecting physical disease (such as venous leg ulcers, Crohn’s disease, urinary tract infection, and chronic heart failure). Placebos also do not work as strongly in clinical trial
s because the subjects do not know whether they might be getting a real treatment or a sham one. Where studies are made of placebos in which people think they are receiving actual treatment (rather than merely its possibility) the placebo effect has been observed. Other writers have argued that the placebo effect can be reliably demonstrated under appropriate conditions.
In another update by Hróbjartsson & Gøtzsche, published as a 2010 Cochrane systematic review which confirms and modifies their previous work, over 200 trials investigating 60 clinical conditions were included. Placebo interventions were again not found to have important clinical effects in general but may influence patient-reported outcomes in some situations, especially pain and nausea, although it was "difficult to distinguish patient-reported effects of placebo from response bias". The pooled relative risk
they calculated for placebo was 0.93 (effect of only 7%) but significant
. Effects were also found for phobia and asthma but were uncertain due to high risk of bias. In other conditions involving three or more trials, there was no statistically significant effect for smoking, dementia, depression, obesity, hypertension, insomnia and anxiety, although confidence interval
s were wide. Several clinical (physical placebos, patient-involved outcomes, falsely informing patients there was no placebo) and methodological (small sample size, explicit aim of studying the placebo effect) factors were associated with higher effects of placebo. Despite low effects in general and the risk of bias, the authors acknowledged that large effects of placebo interventions may occur in certain situations.
nocebo = "I will harm"). In this effect, giving an inert substance has negative consequences.
Another negative consequence is that placebos can cause side-effects
associated with real treatment. 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.
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 40.5% of those on placebo compared to 63.3% of those on hormone replacement.
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. The accompanying editorial concluded, "We cannot afford to dispense with any treatment that works, even if we are not certain how it does." Other researches 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.
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.
The following impracticalities exist with placebos: (See the BMJ posted responses to Spiegel's editorial rapid response online section.)
About 25% of physicians in both the Danish and Israeli studies used placebos as a diagnostic tool to determine if a patient's symptoms were real, or if the patient was malingering
. Both the critics and defenders of the medical use of placebos agreed that this was unethical. The British Medical Journal
editorial said, "That a patient gets pain relief from a placebo does not imply that the pain is not real or organic in origin...the use of the placebo for 'diagnosis' of whether or not pain is real is misguided."
The placebo administration may prove to be a useful treatment in some specific cases where recommended drugs cannot be used. For example, burn patients who are experiencing respiratory problems cannot often be prescribed opioid (morphine
) or opioid derivatives (pethidine
), as these can cause further respiratory depression. In such cases placebo injections (normal saline, etc.) are of use in providing real pain relief to burn patients if those not in delirium are told they are being given a powerful dose of painkiller.
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.
, in a paper in 1955 suggested placebo effects occurred in about 35% of people. However, the response rate is wide, ranging from 0% up to nearly everyone. In a dental postoperative pain model, placebo analgesia occurred in 39%. In research upon ischemic arm pain, placebo analgesia was found in 27%. The placebo analgesia rate for cutaneous healing of left hand skin was 56%.
Though not everyone responds to a placebo, neither does everyone respond to an active drug. The percentage of patients who reported relief following placebo (39%) is similar to the percentage following 4 mg
(36%) and 6 mg (50%) of hidden morphine.
to those that responded to placebos. The findings could not be replicated and it is now thought to have no effect.
The desire for relief from pain, "goal motivation
", and how far pain is expected to be relieved increases placebo analgesia. Another factor increasing the effectiveness of placebos is the degree to which a person attends to their symptoms, "somatic focus". Individual variation in response to analgesic placebos has been linked to regional neurochemical differences in the internal affective state
of the individuals experiencing pain.
Those with Alzheimer’s disease lose the capacity to be influenced by placebos, and this is attributed to the loss of their prefrontal cortex
dependent capacity to have expectations.
Children
seem to have greater response than adults to placebos.
(SAD) an inherited variant
of the gene for tryptophan hydroxylase 2 (enzyme
that synthesizes the neurotransmitter serotonin
) is linked to reduced amygdala
activity and greater susceptibility to the placebo effect.
The authors note "additional work is necessary to elucidate the generalizability of the findings".
has suggested as another factor, that placebos work most strongly upon conditions such as pain, swelling, stomach ulcers, depression, and anxiety that have been linked with activation of the acute-phase response.
.
Most research reports average reduction for a group of people, but this can be lower (some people do not respond). In one study using injection of capsaicin
below the skin found that this reduced group average pain compared to no placebo by ~46% to ~57%. Another measure is the ability to endure pain. In one study, placebos increased this on average by about 3.5 minutes compared to just under 14 minutes without it. The average strength of placebos upon pain on a visual analog scale is 2 out of 10 units. Individuals who respond to placebos may show even greater effects up to 5 out of 10 units.
of published antidepressant trials found that 75% of the effectiveness of anti-depressant medication is due to the placebo effect and other non-specific effects, rather than the treatment itself. Later, meta-analyses including data from unpublished trials found that the overall difference between drug and placebo is not clinically significant except in cases of very extreme depression, 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. A meta-analysis in 2002 found a 30% reduction in suicide
and attempted suicide in the placebo groups compared to a 40% reduction in the treated groups.
A 2002 article in The Washington Post
titled "Against Depression, a Sugar Pill Is Hard to Beat" summarized research as follows: "In the majority of trials conducted by drug companies in recent decades, sugar pills have done as well as -- or better than -- antidepressants. Companies have had to conduct numerous trials to get two that show a positive result, which is the Food and Drug Administration's minimum for approval. The makers of Prozac had to run five trials to obtain two that were positive, and the makers of Paxil and Zoloft had to run even more”.
secretion inhibitor drug cimetidine
in the treatment of gastric or duodenal ulcers found that placebo treatments, in many cases, were as effective as active drugs: of the 1692 patients treated in the 31 trials, 76% of the 916 treated with the drug were "healed", and 48% of the 776 treated with placebo were "healed". These results were confirmed by the direct post-treatment endoscopy
. It was also found that German placebos were "stronger" than others; and that, overall, different physicians evoked quite different placebo responses in the same clinical trial (p. 15). Moreover, in many of these trials the gap between the active drugs and the placebo controls was "not because [the trials' constituents] had high drug effectiveness, but because they had low placebo effectiveness" (p. 13).
In some trials, placebos were effective in 90% of the cases, whereas in others the placebos were effective in only 10% of the cases. It was argued that "what is demonstrated in [these] studies is not enhanced healing in drug groups but reduced healing in placebo groups" (p. 14). It was also noted the results of two studies (one conducted in Germany, the other in Denmark), which examined "ulcer relapse
in healed patients" showed that the rate of relapse amongst those "healed" by the active drug treatment was five times that of those "healed" by the placebo treatment (pp. 14–15).
(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.
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.
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
. 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.
A further issue of concern to pharmaceutical companies is that the effectiveness of placebos has increased over time, thus making it more difficult to demonstrate the effectiveness of new drugs. The reason for the increased effectiveness in disputed.
(Latin
nocebo = "I shall harm") can be measured in the same way as the placebo effect, e.g., when members of a control group receiving an inert substance report a worsening of symptoms. The recipients of the inert substance may nullify the placebo effect intended by simply having a negative attitude towards the effectiveness of the substance prescribed, which often leads to a nocebo effect, which is not caused by the substance, but due to other factors, such as the patient's mentality towards his or her ability to get well, or even purely coincidental worsening of symptoms.
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.
In medical research, placebos are given as 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...
treatments and depend on the use of measured deception. Common placebos are inert tablets, sham surgery
Sham surgery
Sham surgery is a faked operative intervention that omits the step thought to be therapeutically necessary. In controlled studies sham surgery is performed in the control population to assess the effect of the intervention under study by neutralizing the placebo effect and reducing bias...
, and other procedures based on false information. However, placebos can also have a surprisingly positive effect on a patient who knows that the given treatment is without any active drug, as compared with a control group who knowingly did not get a placebo.
In one common placebo procedure, however, a patient is given an inert pill, told that it may improve his/her condition, but not told that it is in fact inert. Such an intervention may cause the patient to believe the treatment will change his/her condition; and this belief may produce a subjective perception of a therapeutic effect
Therapeutic effect
A therapeutic effect is a consequence of a medical treatment of any kind, the results of which are judged to be desirable and beneficial. This is true whether the result was expected, unexpected, or even an unintended consequence of the treatment...
, causing the patient to feel their condition has improved — or an actual improvement in their condition. This phenomenon is known as the placebo effect.
Placebos are widely used in medical research and medicine
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
, and the placebo effect is a pervasive phenomenon; in fact, it is part of the response to any active medical intervention. Archie Cochrane suggested in 1972 "It is important to distinguish the very respectable, conscious use of placebos. The effect of placebos has been shown by randomised controlled trials to be very large. Their use in the correct place is to be encouraged […]"
The placebo effect points to the importance of perception and the brain's role in physical health
Neural top down control of physiology
Neural top down control of physiology concerns the direct regulation by the brain of physiological functions...
. However, when used as treatment in clinical medicine (as opposed to laboratory research), the deception involved in the use of placebos creates tension between 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...
and the honesty of the doctor-patient relationship. The United Kingdom Parliamentary Committee on Science and Technology has stated that: "...prescribing placebos... usually relies on some degree of patient deception" and "prescribing pure placebos is bad medicine. Their effect is unreliable and unpredictable and cannot form the sole basis of any treatment on the NHS."
Since the publication of Henry K. Beecher
Henry K. Beecher
Henry Knowles Beecher was an important figure in the history of anesthesiology and medicine, receiving awards and honors during his career. His 1966 article on unethical practices in medical experimentation within the New England Journal of Medicine was instrumental in the implementation of...
's The Powerful Placebo in 1955, the phenomenon has been considered to have clinically important effects. This view was notably challenged when, in 2001, a systematic review
Systematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...
of clinical trials concluded that there was no evidence of clinically important effects, except perhaps in the treatment of pain and continuous subjective outcomes. The article received a flurry of criticism, but the authors later published a Cochrane
Cochrane Collaboration
The Cochrane Collaboration is a group of over 28,000 volunteers in more than 100 countries who review the effects of health care interventions tested in biomedical randomized controlled trials. A few more recent reviews have also studied the results of non-randomized, observational studies...
review with similar conclusions (updated ). Most studies have attributed the difference from baseline till 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. However these conclusions have been criticized because of the great variety of diseases—more than 40—in this metastudy. The effect of placebo is very different in different diseases. By pooling quite different diseases the results can be levelled out.
Definitions, effects, and ethics
A placebo has been defined as "a substance or procedure… that is objectively without specific activity for the condition being treated". Under this definition, a wide variety of things can be placebos and exhibit a placebo effect. PharmacologicalPharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
substances administered
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is taken into the body.-Classification:Routes of administration are usually classified by application location...
through any means can act as placebos, including pills
Pill (pharmacy)
A pill is a small, round, solid pharmaceutical oral dosage form that was in use before the advent of tablets and capsules. Pills were made by mixing the active ingredients with an excipient such as glucose syrup in a mortar and pestle to form a paste, then rolling the mass into a long cylindrical...
, creams
Cream (pharmaceutical)
A cream is a topical preparation usually for application to the skin. Creams for application to mucus membranes such as those of the rectum or vagina are also used. Creams may be considered pharmaceutical products as even cosmetic creams are based on techniques developed by pharmacy and...
, inhalants
Inhaler
An inhaler or puffer is a medical device used for delivering medication into the body via the lungs. It is mainly used in the treatment of asthma and Chronic Obstructive Pulmonary Disease . Zanamivir , used to treat influenza, must be administered via inhaler...
, and injections
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
. Medical devices such as ultrasound
Therapeutic ultrasound
Therapeutic ultrasound refers generally to any type of procedure that uses ultrasound for therapeutic benefit. This includes HIFU, lithotripsy, targeted ultrasounddrug delivery, trans-dermal ultrasound drug delivery, ultrasound hemostasis, and ultrasound assisted thrombolysis.-Physical...
can act as placebos. Sham surgery
Sham surgery
Sham surgery is a faked operative intervention that omits the step thought to be therapeutically necessary. In controlled studies sham surgery is performed in the control population to assess the effect of the intervention under study by neutralizing the placebo effect and reducing bias...
, sham electrodes implanted in the brain
Chronic Electrode Implants
Chronic Electrode Implants are electronic devices implanted into the brain. They may record electrical impulses in the brain or they may stimulate neurons with electrical impulses from an external source.- Clinical applications and direction :...
, and sham acupuncture, either with sham needles or on fake acupuncture points, have all exhibited placebo effects. Bedding not treated to reduce allergies has been used as a placebo to control for treated bedding. The physician
Physician
A physician is a health care provider who practices the profession of medicine, which is concerned with promoting, maintaining or restoring human health through the study, diagnosis, and treatment of disease, injury and other physical and mental impairments...
has even been called a placebo;33–34 a study found that patient recovery can be increased by words that suggest the patient “would be better in a few days”, and if the patient is given treatment, that “the treatment would certainly make him better” rather than negative words such as “I am not sure that the treatment I am going to give you will have an effect”. The placebo effect may be a component of pharmacological therapies: Pain killing
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
and anxiety reducing drugs
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
that are infused secretly without an individual’s knowledge are less effective than when a patient knows they are receiving them. Likewise, the effects of stimulation from implanted electrodes in the brains of those with advanced Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
are greater when they are aware they are receiving this stimulation. Sometimes administering or prescribing a placebo merges into fake medicine.
The placebo effect has sometimes been defined as a physiological effect caused by the placebo, but Moerman and Jonas have pointed out that this seems illogical, as a placebo is an inert substance that does not directly cause anything. Instead they introduced the word "meaning response" for the meaning that the brain associates with the placebo, which causes a physiological placebo effect. They propose that the placebo, which may be unethical, could be avoided entirely if doctors comfort and encourage their patients' health. Ernst and Resch also attempted to distinguish between the "true" and "perceived" placebo effect, as they argued that some of the effects attributed to the placebo effect could be due to other factors.
The placebo effect has been controversial throughout history. Notable medical organizations have endorsed it, but in 1903 Richard Cabot
Richard Clarke Cabot
Richard Clarke Cabot was an American physician who advanced clinical hematology, was an innovator in teaching methods, and was a pioneer in social work.-Family History:...
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". Another possible resolution of the ethical dilemma might come from the "honest placebo" effect found in a 2010 study carried out by researchers in the Program in Placebo Studies
Program in Placebo Studies
The Program in Placebo Studies and the Therapeutic Encounter was founded in July 2011, at Beth Israel Deaconess Medical Center and the Harvard Medical School...
at the Harvard Medical School
Harvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....
, where patients with irritable bowel syndrome experienced a significant beneficial effect even though they were told the pills they were taking were placebos, as compared to a control group who received no pills.
History
The word 'placebo', Latin for "I will please", dates back to a Latin translation of the Bible by JeromeJerome
Saint Jerome was a Roman Christian priest, confessor, theologian and historian, and who became a Doctor of the Church. He was the son of Eusebius, of the city of Stridon, which was on the border of Dalmatia and Pannonia...
. It was first used in a medicinal context in the 18th century. In 1785 it was defined as a "commonplace method or medicine" and in 1811 it was defined as "any medicine adapted more to please than to benefit the patient", sometimes with a derogatory implication but not with the implication of no effect. Placebos were widespread in medicine until the 20th century, and they were sometimes endorsed as necessary deceptions. In 1903 Richard Cabot
Richard Clarke Cabot
Richard Clarke Cabot was an American physician who advanced clinical hematology, was an innovator in teaching methods, and was a pioneer in social work.-Family History:...
said that he was brought up to use placebos, 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". In 1961 Henry K. Beecher
Henry K. Beecher
Henry Knowles Beecher was an important figure in the history of anesthesiology and medicine, receiving awards and honors during his career. His 1966 article on unethical practices in medical experimentation within the New England Journal of Medicine was instrumental in the implementation of...
found that surgeons he categorized as enthusiasts relieved their patients' chest pain and heart problems more than skeptic surgeons. In 1961 Walter Kennedy introduced the word nocebo
Nocebo
In medicine, a nocebo reaction or response refers to harmful, unpleasant, or undesirable effects a subject manifests after receiving an inert dummy drug or placebo...
. Beginning in the 1960s, the placebo effect became widely recognized and placebo controlled trials became the norm in the approval of new medications. Later, researchers became interested in understanding the placebo effect, rather than just controlling for its effects, and in 2011, a Program in Placebo Studies
Program in Placebo Studies
The Program in Placebo Studies and the Therapeutic Encounter was founded in July 2011, at Beth Israel Deaconess Medical Center and the Harvard Medical School...
was established at the Harvard Medical School
Harvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....
.
Mechanism of the effect
The phenomenon of an inert substance's resulting in a patient's medical improvement is called the placebo effect. The phenomenon is related to the perception and expectation that the patient has; if the substance is viewed as helpful, it can heal, but, if it is viewed as harmful, it can cause negative effects, which is known as the noceboNocebo
In medicine, a nocebo reaction or response refers to harmful, unpleasant, or undesirable effects a subject manifests after receiving an inert dummy drug or placebo...
effect. The basic mechanisms of placebo effects have been investigated since 1978, when it was found that the opioid antagonist naloxone
Naloxone
Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...
could block placebo painkillers, suggesting that endogenous opioids are involved.
Expectancy and conditioning
In 1985, Irving KirschIrving Kirsch
Irving Kirsch is Associate Director of the Program in Placebo Studies and a lecturer in medicine at the Harvard Medical School and Beth Israel Deaconess Medical Center. He is also a professor emeritus of psychology at the University of Hull, United Kingdom and the University of Connecticut in the...
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. 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
Classical conditioning
Classical conditioning is a form of conditioning that was first demonstrated by Ivan Pavlov...
, wherein a placebo and an actual stimulus are used simultaneously until the placebo is associated with the effect from the actual stimulus. Both conditioning and expectations play a role in placebo effect, and make different kinds of contribution. Conditioning has a longer-lasting effect, and can affect earlier stages of information processing. The expectancy effect can be enhanced through factors such as the enthusiasm of the doctor, differences in size and color of placebo pills, or the use of other interventions such as injections. In one study, the response to a placebo increased from 44% to 62% when the doctor treated them with "warmth, attention, and confidence". Expectancy effects have been found to occur with a range of substances. 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.
Because the placebo effect is based upon expectations and conditioning, the effect disappears if the patient is told that their expectations are unrealistic, or that the placebo intervention is ineffective. A conditioned pain reduction can be totally removed when its existence is explained. It has also been reported of subjects given placebos in a trial of anti-depressants, that "Once the trial was over and the patients who had been given placebos were told as much, they quickly deteriorated."
A placebo described as a muscle relaxant
Muscle relaxant
A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
will cause muscle relaxation and, if described as the opposite, muscle tension. A placebo presented as a stimulant
Stimulant
Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
will have this effect on heart rhythm
Heart Rhythm
Heart Rhythm is a peer-reviewed medical journal that covers the study and management of cardiac arrhythmia. It is the official journal of the Heart Rhythm Society and the Cardiac Electrophysiology Society...
, and blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
, but, when administered as a depressant
Depressant
A depressant, or central depressant, is a drug or endogenous compound that depresses the function or activity of a specific part of the brain...
, the opposite effect. The perceived consumption of caffeine has been reported to cause similar effects even when decaffeinated coffee is consumed, although a 2003 study found only limited support for this. Alcohol placebos can cause intoxication and sensorimotor impairment. Perceived ergogenic aids can increase endurance, speed and weight-lifting ability, leading to the question of whether placebos should be allowed in sport competition. Placebos can help smokers quit. Perceived allergens that are not truly allergenic can cause allergies. Interventions such as psychotherapy can have placebo effects.pp 164–173 The effect has been observed in the transplantation of human embryonic neurons into the brains of those with advanced Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
.
Because placebos are dependent upon perception and expectation, various factors that change the perception can increase the magnitude of the placebo response. For example, studies have found that the color and size of the placebo pill makes a difference, with "hot-colored" pills working better as stimulants while "cool-colored" pills work better as depressants. Capsules rather than tablet
Tablet
A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose...
s seem to be more effective, and size can make a difference. One researcher has found that big pills increase the effect while another has argued that the effect is dependent upon cultural background. More pills, branding, past experience, and high price increase the effect of placebo pills. Injection and acupuncture
Acupuncture
Acupuncture is a type of alternative medicine that treats patients by insertion and manipulation of solid, generally thin needles in the body....
have larger effect than pills. Proper adherence to placebos is associated with decreased mortality.
Motivation
Motivation
Motivation is the driving force by which humans achieve their goals. Motivation is said to be intrinsic or extrinsic. The term is generally used for humans but it can also be used to describe the causes for animal behavior as well. This article refers to human motivation...
may contribute to the placebo effect. The active goals of an individual changes his/her somatic experience by altering the detection and interpretation of expectation-congruent symptoms, and by changing the behavioral strategies a person pursues. 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. Research upon the placebo treatment of gastric and duodenal ulcers shows that this varies widely with society: those in Germany having a high-rate placebo effect while those in Brazil a low one. Placebo effects in treating gastric ulcers is low in Brazil, higher in northern Europe (Denmark, Netherlands), and extremely high in Germany. But the placebo effect for hypertension is lower in Germany than elsewhere Social observation can induce a placebo effect such when a person sees another having reduced pain following what they believe is a pain reducing procedure.
The placebo effect can work selectively. If an analgesic placebo cream is applied on one hand, it will reduce pain only in that hand and not elsewhere on the body 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.
Placebo effect and the brain
Functional imagingFunctional imaging
Functional imaging , is a method of detecting or measuring changes in metabolism, blood flow, regional chemical composition, and absorption....
upon placebo analgesia shows that it links to the activation, and increased functional correlation between this activation, in the anterior cingulate, prefrontal
Prefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
, orbitofrontal
Orbitofrontal cortex
The orbitofrontal cortex is a prefrontal cortex region in the frontal lobes in the brain which is involved in the cognitive processing of decision-making...
and insular
Insular cortex
In each hemisphere of the mammalian brain the insular cortex is a portion of the cerebral cortex folded deep within the lateral sulcus between the temporal lobe and the frontal lobe. The cortical area overlying it towards the lateral surface of the brain is the operculum...
cortices, nucleus accumbens
Nucleus accumbens
The nucleus accumbens , also known as the accumbens nucleus or as the nucleus accumbens septi , is a collection of neurons and forms the main part of the ventral striatum...
, amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
, the brainstem periaqueductal gray matter, and the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
.
These changes can act upon the brain’s early stages of information processing: Research using evoked brain potentials
Event-related potential
An event-related potential is any measured brain response that is directly the result of a thought or perception. More formally, it is any stereotyped electrophysiological response to an internal or external stimulus....
upon painful laser pulses, for example, finds placebo effects upon the N2–P2, a biphasic negative–positive complex response, the N2 peak of which is at about 230 ms, and the P2 one at about 380 ms. They occur not only during placebo analgesia but after receiving the analgesic placebo (the areas are different here, and involve the medial prefrontal cortex, posterior parietal cortex
Posterior parietal cortex
The posterior parietal cortex plays an important role in producing planned movements. Before an effective movement can be initiated, the nervous system must know the original positions of the body parts that are to be moved, and the positions of any external objects with which the body is going to...
and inferior parietal lobule).
Different areas in the higher brain have different functions. The prefrontal involvement could be related to recalling the placebo and maintaining its cognitive presence in a "self-reinforcing feedback loop" (during pain an individual recalls having taken the placebo and reduced pain reinforces its status as an analgesic). The rostral anterior cingulate cortex (rACC) and its subcortical connectivity could be related to the expectation of potential pain stimuli
The higher brain works by regulating subcortical processes. High placebo responses link with enhanced dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and mu-opioid
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...
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. (It has been known that placebo analgesia depends upon the release in the brain of endogenous opioids since 1978.) Such analgesic placebos activation changes processing lower down in the brain by enhancing the descending inhibition through the periaqueductal gray on spinal nociceptive reflexes
Withdrawal reflex
The withdrawal reflex is a spinal reflex intended to protect the body from damaging stimuli...
, while the expectations of anti-analgesic nocebos acts in the opposite way to block this.
The brain is also involved in less-studied ways upon nonanalgesic placebo effects:
- Parkinson's diseaseParkinson's diseaseParkinson's disease is a degenerative disorder of the central nervous system...
: Placebo relief is associated with the release of dopamineDopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
in the brain. - DepressionDepression (mood)Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
: Placebos reducing depression affect many of the same areas that are activated by antidepressants with the addition of the prefrontal cortex - CaffeineCaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
: Placebo-caffeinated coffee causes an increase in bilateral dopamine release in the thalamus. - GlucoseGlucoseGlucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
: The expectation of an intravenous injection of glucose increases the release of dopamine in the basal ganglia of men (but not women). - MethylphenidateMethylphenidateMethylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...
: The expectation of intravenous injection of this drug in inexperienced drug users increased the release of dopamine in the ventral cingulate gyrus and nucleus accumbens, with this effect being largest in those with no prior experience of the drug.
Present 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". "Diseases lacking major 'top-down' or cortically based regulation may be less prone to placebo-related improvement".
Brain and body
The brain has control over the body processes affected by placebos. Pain, motor fatigueMuscle weakness
Muscle weakness or myasthenia is a lack of muscle strength. The causes are many and can be divided into conditions that have true or perceived muscle weakness...
, and fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
are directly organized by the brain. Other processes usually regulated by the body such as the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
are also controlled indirectly through the sympathetic and parasympathetic nervous system.
Research upon conditioning
Classical conditioning
Classical conditioning is a form of conditioning that was first demonstrated by Ivan Pavlov...
in animals shows the brain can learn control over them. In conditioning, a neutral stimulus saccharin
Saccharin
Saccharin is an artificial sweetener. The basic substance, benzoic sulfilimine, has effectively no food energy and is much sweeter than sucrose, but has a bitter or metallic aftertaste, especially at high concentrations...
is paired in a drink with an agent that produces an unconditioned response. For example, that agent might be cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
that causes immunosuppression. After learning this pairing, the taste of saccharin by itself through neural top-down control created immunosuppression, as a new conditioned response. 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
Serum iron
Serum iron is a medical laboratory test that measures the amount of circulating iron that is bound to transferrin. Clinicians order this laboratory test when they are concerned about iron deficiency, which can cause anemia and other problems....
, oxidative DNA damage
DNA oxidation
DNA oxidation is the process of oxidative damage on Deoxyribonucleic Acid. It occurs most readily at guanine residues due to the high oxidation potential of this base relative to cytosine, thymine, and adenine. It is widely believed to be linked to certain disease and cancers.-RNA Oxidation:RNAs in...
levels, and insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
secretion. This work was originally done on rats, however the same conditioning of basic physiological processes can also occur in humans. Recent reviews have argued the placebo effect is due to top-down control by the brain for immunity and pain. 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."pp 441
A recent fMRI study has shown that a placebo can reduce pain-related neural activity in the spinal cord, indicating that placebo effects can extend beyond the brain.
Evolved health regulation
Evolutionary medicineEvolutionary medicine
Evolutionary medicine or Darwinian medicine is the application of modern evolutionary theory to understanding health and disease. It provides a complementary scientific approach to the present mechanistic explanations that dominate medical science, and particularly modern medical education...
identifies many symptoms such as fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
, and sickness behavior
Sickness behavior
thumb|350px|right|[[Michael Peter Ancher|Ancher, Michael]], "The Sick Girl", 1882, [[Statens Museum for Kunst]]Sickness behavior is a coordinated set of adaptive behavioral changes that develop in ill individuals during the course of an infection....
as evolved responses to protect or enhance the recovery from infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
and injury
Injury
-By cause:*Traumatic injury, a body wound or shock produced by sudden physical injury, as from violence or accident*Other injuries from external physical causes, such as radiation injury, burn injury or frostbite*Injury from infection...
. Fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, for example, is an evolved self-treatment that removes bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
or viruses through raised body temperature
Hyperthermia
Hyperthermia is an elevated body temperature due to failed thermoregulation. Hyperthermia occurs when the body produces or absorbs more heat than it can dissipate...
. These evolved
Adaptation
An adaptation in biology is a trait with a current functional role in the life history of an organism that is maintained and evolved by means of natural selection. An adaptation refers to both the current state of being adapted and to the dynamic evolutionary process that leads to the adaptation....
responses, however, also have a cost
Deployment cost-benefit selection in physiology
Deployment cost–benefit selection in physiology concerns the costs and benefits of physiological process that can be deployed and selected in regard to whether they will increase or not an animal’s survival and biological fitness...
that depending upon circumstances can outweigh their benefit (due to this, for example, there is a reduction in fever during malnutrition
Malnutrition
Malnutrition is the condition that results from taking an unbalanced diet in which certain nutrients are lacking, in excess , or in the wrong proportions....
or late pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
). According to the health management system
Health management system
The health management system is an evolutionary medicine regulative process proposed by Nicholas Humphrey in which actuarial assessment of fitness and economic-type cost-benefit analysis determines the body’s regulation of its physiology and health...
theory proposed by Nicholas Humphrey
Nicholas Humphrey
Professor Nicholas Keynes Humphrey is an English psychologist, based in Cambridge, who is known for his work on the evolution of human intelligence and consciousness. His interests are wide ranging...
, the brain has been selected to ensure that evolved responses are deployed only when the cost benefit
Cost-benefit analysis
Cost–benefit analysis , sometimes called benefit–cost analysis , is a systematic process for calculating and comparing benefits and costs of a project for two purposes: to determine if it is a sound investment , to see how it compares with alternate projects...
is biologically advantageous. To do this, the brain factors in a variety of information sources, including the likelihood derived from beliefs that the body will get well without deploying its costly evolved responses. One such source of information is the knowledge the body is receiving care and treatment. The placebo effect in this perspective arises when false information about medications misleads the health management system about the likelihood of getting well so that it selects not to deploy an evolved self-treatment.
Duration
Placebo effects can last for a long time: over 8 weeks for panic disorderPanic disorder
Panic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
,
6 months for angina pectoris, and two and half years for rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
. Placebo effects after verbal suggestion for mild pain can be robust and still exist after being repeated ten times even if they have no actual pharmacological pain killing action.
Clinical significance
Hróbjartsson and Peter Gøtzsche published a study in 2001 and a follow-up study in 2004 questioning the nature of the placebo effect. The studies were performed as two meta-analysesMeta-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...
. They found that in studies with a binary outcome, meaning patients were classified as improved or not improved, the placebo group had no statistically significant improvement over the no-treatment group. Likewise, there was no significant placebo effect in studies in which objective
Objectivity (science)
Objectivity in science is a value that informs how science is practiced and how scientific truths are created. It is the idea that scientists, in attempting to uncover truths about the natural world, must aspire to eliminate personal biases, a priori commitments, emotional involvement, etc...
outcomes (such as blood pressure) were measured by an independent observer. The placebo effect could be documented only in studies in which the outcomes (improvement or failure to improve) were reported by the subjects themselves. The authors concluded that the placebo effect does not have "powerful clinical effects," (objective effects) and that patient-reported improvements (subjective effects) in pain were small and could not be clearly distinguished from reporting bias
Reporting bias
In empirical research, reporting bias refers to a tendency to under-report unexpected or undesirable experimental results, attributing the results to sampling or measurement error, while being more trusting of expected or desirable results, though these may be subject to the same sources of error...
. Other researchers (Wampold et al.) re-analysed the same data from the 2001 meta-analysis and concluded that the placebo effects for objective symptom measures are comparable to placebo effects for subjective ones and that the placebo effect can exceed the effect of the active treatment by 20% for disorders amenable to the placebo effect, a conclusion which Hróbjartsson & Gøtzsche described as "powerful spin". Another group of researchers noted the dramatically different conclusions between these two sets of authors despite nearly identical meta-analytic results, and suggested that placebo effects are indeed significant but small in magnitude.
Hróbjartsson and Gøtzsche's conclusion has been criticised on several grounds. Their meta-analysis covered studies into a highly mixed group of conditions: The placebo effect does occur with peripheral disease processes (such as hypertension, asthma, prostatic hyperplasia, anal fissure, bronchitis), though not for processes reflecting physical disease (such as venous leg ulcers, Crohn’s disease, urinary tract infection, and chronic heart failure). Placebos also do not work as strongly in 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 because the subjects do not know whether they might be getting a real treatment or a sham one. Where studies are made of placebos in which people think they are receiving actual treatment (rather than merely its possibility) the placebo effect has been observed. Other writers have argued that the placebo effect can be reliably demonstrated under appropriate conditions.
In another update by Hróbjartsson & Gøtzsche, published as a 2010 Cochrane systematic review which confirms and modifies their previous work, over 200 trials investigating 60 clinical conditions were included. Placebo interventions were again not found to have important clinical effects in general but may influence patient-reported outcomes in some situations, especially pain and nausea, although it was "difficult to distinguish patient-reported effects of placebo from response bias". The pooled relative risk
Relative risk
In statistics and mathematical epidemiology, relative risk is the risk of an event relative to exposure. Relative risk is a ratio of the probability of the event occurring in the exposed group versus a non-exposed group....
they calculated for placebo was 0.93 (effect of only 7%) but significant
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
. Effects were also found for phobia and asthma but were uncertain due to high risk of bias. In other conditions involving three or more trials, there was no statistically significant effect for smoking, dementia, depression, obesity, hypertension, insomnia and anxiety, although confidence interval
Confidence interval
In statistics, a confidence interval is a particular kind of interval estimate of a population parameter and is used to indicate the reliability of an estimate. It is an observed interval , in principle different from sample to sample, that frequently includes the parameter of interest, if the...
s were wide. Several clinical (physical placebos, patient-involved outcomes, falsely informing patients there was no placebo) and methodological (small sample size, explicit aim of studying the placebo effect) factors were associated with higher effects of placebo. Despite low effects in general and the risk of bias, the authors acknowledged that large effects of placebo interventions may occur in certain situations.
Negative effects
Similar to the placebo effect, inert substances have the potential to cause negative effects via the "nocebo effect" (LatinLatin
Latin is an Italic language originally spoken in Latium and Ancient Rome. It, along with most European languages, is a descendant of the ancient Proto-Indo-European language. Although it is considered a dead language, a number of scholars and members of the Christian clergy speak it fluently, and...
nocebo = "I will harm"). In this effect, giving an inert substance has negative consequences.
Another negative consequence is that placebos can cause side-effects
Adverse effect (medicine)
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
associated with real treatment. 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.
Withdrawal symptoms can also occur after placebo treatment. This was found, for example, after the discontinuation of the Women's Health Initiative
Women's Health Initiative
The Women's Health Initiative was initiated by the U.S. National Institutes of Health in 1991. The objective of this women's health research initiative was to conduct medical research into some of the major health problems of older women...
study of hormone replacement therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
for menopause
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
. Women had been on placebo for an average of 5.7 years. Moderate or severe withdrawal
Withdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
symptoms were reported by 40.5% of those on placebo compared to 63.3% of those on hormone replacement.
Doctor-patient relationship
A study of Danish general practitioners found that 48% had prescribed a placebo at least 10 times in the past year. The most frequently prescribed placebos were 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 JournalBritish Medical Journal
BMJ is a partially open-access peer-reviewed medical journal. Originally called the British Medical Journal, the title was officially shortened to BMJ in 1988. The journal is published by the BMJ Group, a wholly owned subsidiary of the British Medical Association...
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. The accompanying editorial concluded, "We cannot afford to dispense with any treatment that works, even if we are not certain how it does." Other researches 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.
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.
The following impracticalities exist with placebos: (See the BMJ posted responses to Spiegel's editorial rapid response online section.)
- Roughly only 30% of the population seems susceptible to placebo effects, and it is not possible to determine ahead of time whether a placebo will work or not. (However the placebo effect is zero in studies of blood poisoning and up to 80% in studies of wound on the duodenum).
- Patients rightfully want immediate relief or improvement from their illness or symptoms. A non-placebo can often provide that, while a placebo might not.
- Legitimate doctors and pharmacists could open themselves up to charges of fraud since sugar pills would cost pennies or cents for a bottle, but the price for a "real" medication would have to be charged to avoid making the patient suspicious.
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
Malingering
Malingering is a medical term that refers to fabricating or exaggerating the symptoms of mental or physical disorders for a variety of "secondary gain" motives, which may include financial compensation ; avoiding school, work or military service; obtaining drugs; getting lighter criminal sentences;...
. Both the critics and defenders of the medical use of placebos agreed that this was unethical. The British Medical Journal
British Medical Journal
BMJ is a partially open-access peer-reviewed medical journal. Originally called the British Medical Journal, the title was officially shortened to BMJ in 1988. The journal is published by the BMJ Group, a wholly owned subsidiary of the British Medical Association...
editorial said, "That a patient gets pain relief from a placebo does not imply that the pain is not real or organic in origin...the use of the placebo for 'diagnosis' of whether or not pain is real is misguided."
The placebo administration may prove to be a useful treatment in some specific cases where recommended drugs cannot be used. For example, burn patients who are experiencing respiratory problems cannot often be prescribed opioid (morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
) or opioid derivatives (pethidine
Pethidine
Pethidine or meperidine Pethidine (INN) or meperidine (USAN) Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);...
), as these can cause further respiratory depression. In such cases placebo injections (normal saline, etc.) are of use in providing real pain relief to burn patients if those not in delirium are told they are being given a powerful dose of painkiller.
Referring specifically to homeopathy
Homeopathy
Homeopathy is a form of alternative medicine in which practitioners claim to treat patients using highly diluted preparations that are believed to cause healthy people to exhibit symptoms that are similar to those exhibited by the patient...
, 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.
Who is affected
Placebos do not work for everyone. Henry K. BeecherHenry K. Beecher
Henry Knowles Beecher was an important figure in the history of anesthesiology and medicine, receiving awards and honors during his career. His 1966 article on unethical practices in medical experimentation within the New England Journal of Medicine was instrumental in the implementation of...
, in a paper in 1955 suggested placebo effects occurred in about 35% of people. However, the response rate is wide, ranging from 0% up to nearly everyone. In a dental postoperative pain model, placebo analgesia occurred in 39%. In research upon ischemic arm pain, placebo analgesia was found in 27%. The placebo analgesia rate for cutaneous healing of left hand skin was 56%.
Though not everyone responds to a placebo, neither does everyone respond to an active drug. The percentage of patients who reported relief following placebo (39%) is similar to the percentage following 4 mg
(36%) and 6 mg (50%) of hidden morphine.
Individual differences
In the 1950s, there was considerable research to find whether there was a specific personalityPersonality type
Personality type refers to the psychological classification of different types of individuals. Personality types are sometimes distinguished from personality traits, with the latter embodying a smaller grouping of behavioral tendencies. Types are sometimes said to involve qualitative differences...
to those that responded to placebos. The findings could not be replicated and it is now thought to have no effect.
The desire for relief from pain, "goal motivation
Motivation
Motivation is the driving force by which humans achieve their goals. Motivation is said to be intrinsic or extrinsic. The term is generally used for humans but it can also be used to describe the causes for animal behavior as well. This article refers to human motivation...
", and how far pain is expected to be relieved increases placebo analgesia. Another factor increasing the effectiveness of placebos is the degree to which a person attends to their symptoms, "somatic focus". Individual variation in response to analgesic placebos has been linked to regional neurochemical differences in the internal affective state
Affect (psychology)
Affect refers to the experience of feeling or emotion. Affect is a key part of the process of an organism's interaction with stimuli. The word also refers sometimes to affect display, which is "a facial, vocal, or gestural behavior that serves as an indicator of affect" .The affective domain...
of the individuals experiencing pain.
Those with Alzheimer’s disease lose the capacity to be influenced by placebos, and this is attributed to the loss of their prefrontal cortex
Prefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
dependent capacity to have expectations.
Children
Childhood
Childhood is the age span ranging from birth to adolescence. In developmental psychology, childhood is divided up into the developmental stages of toddlerhood , early childhood , middle childhood , and adolescence .- Age ranges of childhood :The term childhood is non-specific and can imply a...
seem to have greater response than adults to placebos.
Genes
In social anxiety disorderSocial anxiety disorder
Social anxiety disorder , also known as social phobia, is an anxiety disorder characterized by intense fear in social situations causing considerable distress and impaired ability to function in at least some parts of daily life...
(SAD) an inherited variant
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
of the gene for tryptophan hydroxylase 2 (enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that synthesizes the neurotransmitter serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
) is linked to reduced amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
activity and greater susceptibility to the placebo effect.
The authors note "additional work is necessary to elucidate the generalizability of the findings".
Symptoms and conditions
The placebo effect occurs more strongly in some conditions than others. One study found placebo effects are most likely to be found with the peripheral aspects of disease processes, rather than processes that reflect physical disease. Dylan EvansDylan Evans
Dylan Evans is a British academic and author who has written books on emotion and the placebo effect as well as the theories of Jacques Lacan.-Early life and education:...
has suggested as another factor, that placebos work most strongly upon conditions such as pain, swelling, stomach ulcers, depression, and anxiety that have been linked with activation of the acute-phase response.
Pain
Placebo analgesia is more likely to work the more severe the pain. One study found that for postoperative pain following the extraction of the third molar, saline injected while telling the patient it was a powerful painkiller was as potent as a 6–8 mg dose of morphineMorphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
.
Most research reports average reduction for a group of people, but this can be lower (some people do not respond). In one study using injection of capsaicin
Capsaicin
Capsaicin 2CHCH=CH4CONHCH2C6H3-4--3- ) is the active component of chili peppers, which are plants belonging to the genus Capsicum. It is an irritant for mammals, including humans, and produces a sensation of burning in any tissue with which it comes into contact...
below the skin found that this reduced group average pain compared to no placebo by ~46% to ~57%. Another measure is the ability to endure pain. In one study, placebos increased this on average by about 3.5 minutes compared to just under 14 minutes without it. The average strength of placebos upon pain on a visual analog scale is 2 out of 10 units. Individuals who respond to placebos may show even greater effects up to 5 out of 10 units.
Depression
In 1998, a meta-analysisMeta-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 published antidepressant trials found that 75% of the effectiveness of anti-depressant medication is due to the placebo effect and other non-specific effects, rather than the treatment itself. Later, meta-analyses including data from unpublished trials found that the overall difference between drug and placebo is not clinically significant except in cases of very extreme depression, 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. A meta-analysis in 2002 found a 30% reduction in suicide
Suicide
Suicide is the act of intentionally causing one's own death. Suicide is often committed out of despair or attributed to some underlying mental disorder, such as depression, bipolar disorder, schizophrenia, alcoholism, or drug abuse...
and attempted suicide in the placebo groups compared to a 40% reduction in the treated groups.
A 2002 article in The Washington Post
The Washington Post
The Washington Post is Washington, D.C.'s largest newspaper and its oldest still-existing paper, founded in 1877. Located in the capital of the United States, The Post has a particular emphasis on national politics. D.C., Maryland, and Virginia editions are printed for daily circulation...
titled "Against Depression, a Sugar Pill Is Hard to Beat" summarized research as follows: "In the majority of trials conducted by drug companies in recent decades, sugar pills have done as well as -- or better than -- antidepressants. Companies have had to conduct numerous trials to get two that show a positive result, which is the Food and Drug Administration's minimum for approval. The makers of Prozac had to run five trials to obtain two that were positive, and the makers of Paxil and Zoloft had to run even more”.
Gastric and duodenal ulcers
A meta-study of 31 placebo-controlled trials of the gastric acidGastric acid
Gastric acid is a digestive fluid, formed in the stomach. It has a pH of 1 to 2 and is composed of hydrochloric acid , and large quantities of potassium chloride and sodium chloride...
secretion inhibitor drug cimetidine
Cimetidine
Cimetidine INN is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet...
in the treatment of gastric or duodenal ulcers found that placebo treatments, in many cases, were as effective as active drugs: of the 1692 patients treated in the 31 trials, 76% of the 916 treated with the drug were "healed", and 48% of the 776 treated with placebo were "healed". These results were confirmed by the direct post-treatment endoscopy
Endoscopy
Endoscopy means looking inside and typically refers to looking inside the body for medical reasons using an endoscope , an instrument used to examine the interior of a hollow organ or cavity of the body. Unlike most other medical imaging devices, endoscopes are inserted directly into the organ...
. It was also found that German placebos were "stronger" than others; and that, overall, different physicians evoked quite different placebo responses in the same clinical trial (p. 15). Moreover, in many of these trials the gap between the active drugs and the placebo controls was "not because [the trials' constituents] had high drug effectiveness, but because they had low placebo effectiveness" (p. 13).
In some trials, placebos were effective in 90% of the cases, whereas in others the placebos were effective in only 10% of the cases. It was argued that "what is demonstrated in [these] studies is not enhanced healing in drug groups but reduced healing in placebo groups" (p. 14). It was also noted the results of two studies (one conducted in Germany, the other in Denmark), which examined "ulcer relapse
Relapse
Relapse, in relation to drug misuse, is resuming the use of a drug or a dependent substance after one or more periods of abstinence. The term is a landmark feature of both substance dependence and substance abuse, which are learned behaviors, and is maintained by neuronal adaptations that mediate...
in healed patients" showed that the rate of relapse amongst those "healed" by the active drug treatment was five times that of those "healed" by the placebo treatment (pp. 14–15).
Chronic fatigue syndrome
It was previously assumed that placebo response rates in patients with chronic fatigue syndromeChronic fatigue syndrome
Chronic fatigue syndrome is the most common name used to designate a significantly debilitating medical disorder or group of disorders generally defined by persistent fatigue accompanied by other specific symptoms for a minimum of six months, not due to ongoing exertion, not substantially...
(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.
List of medical conditions
The effect of placebo treatments (an inert pill unless otherwise noted) has been studied for the following medical conditions:- ADHD: adult, child
- Amalgam fillingsAmalgam (dentistry)Amalgam is an alloy containing mercury. The term is commonly used for the amalgam employed as material for dental fillings, which consists of mercury , silver , tin , copper , and other trace metals...
: attributed symptoms (inert "chelation" therapy) - Anxiety disorders
- AsthmaAsthmaAsthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
(water aerosol inhalant) - AsthmaAsthmaAsthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
- AutismAutismAutism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
: language and behavior problems - Benign prostatic enlargement
- Binge eating disorderBinge eating disorderBinge eating disorder is the most common eating disorder in the United States affecting 3.5% of females and 2% of males and is prevalent in up to 30% of those seeking weight loss treatment...
- Bipolar mania
- CoughCoughA cough is a sudden and often repetitively occurring reflex which helps to clear the large breathing passages from secretions, irritants, foreign particles and microbes...
- Crohn's diseaseCrohn's diseaseCrohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
- DepressionDepression (mood)Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
(light treatment; low red light placebo) - DepressionDepression (mood)Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
- DyspepsiaDyspepsiaDyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...
and Stomach motility - EpilepsyEpilepsyEpilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
- Erectile dysfunctionErectile dysfunctionErectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
- Food allergyFood allergyA food allergy is an adverse immune response to a food protein. They are distinct from other adverse responses to food, such as food intolerance, pharmacological reactions, and toxin-mediated reactions....
: ability to eat ill-making foods - Gastric and duodenal ulcersPeptic ulcerA peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
- HeadacheHeadacheA 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...
- Heart failure, congestive
- Herpes simplex
- HypertensionHypertensionHypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
: mild and moderate - Irritable bowel syndromeIrritable bowel syndromeIrritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
- MigraineMigraineMigraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
prophylaxis - Multiple sclerosisMultiple sclerosisMultiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
- NauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
: gastric activity - NauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
: chemotherapy - NauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomitingVomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
: postoperative (sham acupuncture) - PainPainPain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
- PanicPanicPanic is a sudden sensation of fear which is so strong as to dominate or prevent reason and logical thinking, replacing it with overwhelming feelings of anxiety and frantic agitation consistent with an animalistic fight-or-flight reaction...
disorders - Parkinson's diseaseParkinson's diseaseParkinson's disease is a degenerative disorder of the central nervous system...
- Pathological gambling
- Premenstrual dysphoric disorderPremenstrual dysphoric disorderPremenstrual dysphoric disorder is a severe form of premenstrual syndrome, afflicting 3% to 8% of women. It is a diagnosis associated primarily with the luteal phase of the menstrual cycle...
. - Psoriatic arthritisPsoriatic arthritisPsoriatic arthritis is a type of inflammatory arthritis that, according to the National Psoriasis Foundation, will develop in up to 30 percent of people who have the chronic skin condition psoriasis...
- Reflux esophagitisEsophagitisEsophagitis is inflammation of the esophagus. It may be acute or chronic. The acute esophagitis can be catarrhal or phlegmonous, whereas the chronic esophagitis may be hypertrophic or atrophic.-Infectious:...
- Restless leg syndrome
- Rheumatic diseases
- Sexual dysfunctionSexual dysfunctionSexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
: women - Social phobia
- Third molarThird molarA wisdom tooth, in humans, is any of the usually four third molars. Wisdom teeth usually appear between the ages of 17 and 25. Most adults have four wisdom teeth, but it is possible to have fewer , or more, in which case they are called supernumerary teeth...
extraction swelling (sham ultra-sound) - Ulcerative colitisUlcerative colitisUlcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the colon , that includes characteristic ulcers, or open sores. The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual onset...
- Vulvar vestibulitisVulvar vestibulitisVulvar Vestibulitis Syndrome , vestibulodynia, or simply vulvar vestibulitis is vulvodynia localized to the vulvar region. It tends to be associated with a highly localized “burning” or “cutting” type of pain....
Placebo-controlled studies
The placebo effect makes it more difficult to evaluate new treatments. Apparent benefits of a new treatment (usually a drug but not necessarily so) may not derive from the treatment but from the placebo effect. This is particularly likely, given that new therapies seem to have greater placebo effects. 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. 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.
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
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...
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
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...
. 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.
A further issue of concern to pharmaceutical companies is that the effectiveness of placebos has increased over time, thus making it more difficult to demonstrate the effectiveness of new drugs. The reason for the increased effectiveness in disputed.
Nocebo
In the opposite effect, a patient who disbelieves in a treatment may experience a worsening of symptoms. This effect, now called by analogy noceboNocebo
In medicine, a nocebo reaction or response refers to harmful, unpleasant, or undesirable effects a subject manifests after receiving an inert dummy drug or placebo...
(Latin
Latin
Latin is an Italic language originally spoken in Latium and Ancient Rome. It, along with most European languages, is a descendant of the ancient Proto-Indo-European language. Although it is considered a dead language, a number of scholars and members of the Christian clergy speak it fluently, and...
nocebo = "I shall harm") can be measured in the same way as the placebo effect, e.g., when members of a control group receiving an inert substance report a worsening of symptoms. The recipients of the inert substance may nullify the placebo effect intended by simply having a negative attitude towards the effectiveness of the substance prescribed, which often leads to a nocebo effect, which is not caused by the substance, but due to other factors, such as the patient's mentality towards his or her ability to get well, or even purely coincidental worsening of symptoms.
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 affected the results. For example, one study on cholesterol-lowering drugs used olive oilOlive 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.
External links
- Program in Placebo Studies at the Harvard Medical School
- The Placebo Effect at the Skeptic's Dictionary
- The Placebo Effect explained on YouTube
- Placebos: cracking the code part 1 part 2 BBC/Discovery channel program
- "The Placebo Effect: Do You Believe Your Teacher?" Ben Goldacre on The Guardian and on Wikibooks.
- "Placebos are getting more effective. Drugmakers are desperate to know why." Wired magazine on the power of the placebo. Retrieved 2010-07-22
- Biological, clinical, and ethical advances of placebo effects The Lancet (2010)