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Placebo effect
or Beleive and so shall it be!
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A placebo (/pləˈsiboʊ/
plə-SEE-boh;
Latin
placēbō,
"I shall please"[2]
from placeō,
"I please")[3][4]
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. Placebo effect consists of several
different effects woven together, and the methods of placebo
administration may be as important as the administration itself.[5]
In medical research, placebos are given as control
treatments and depend on the use of measured suggestion. Common
placebos include inert tablets, vehicle infusions, sham
surgery,[6]
and other procedures based on false information.[1]
However, placebos may also have positive effect on the subjective
experience of 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.[7]
It has also been shown that use of therapies about which patients are
unaware is less effective than using ones that patients are informed
about.[8]
Placebo effects are the subject of scientific research aiming to
understand underlying neurobiological mechanisms of action in pain
relief, immunosuppression,
Parkinson's
disease and depression.[9]
Brain imaging techniques done by Emeran
Mayer, Johanna Jarco and Matt Lieberman showed that placebo can
have real, measurable effects on physiological changes in the
brain.[10]
Some objective physiological changes have been reported, from changes
in heart rate and blood pressure to chemical activity in the brain,
in cases involving pain, depression, anxiety, fatigue, and some
symptoms of Parkinson’s, but in other cases, like asthma, the
effect is purely subjective, when the patient reports improvement
despite no objective change in the underlying condition.[11]
Placebos are widely used in medical
research and medicine,[12]
and the placebo effect is a pervasive phenomenon;[12]
in fact, it is part of the response to any active medical
intervention.[13]
The placebo effect points to the importance of perception and the
brain's role in physical health. However, the use of placebos as
treatment in clinical medicine (as opposed to laboratory research) is
ethically problematic as it introduces deception and dishonesty into
the doctor-patient relationship.[14]
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."[15]
Since the publication of Henry
K. Beecher's The Powerful Placebo[16]
in 1955, the phenomenon has been considered to have clinically
important effects.[17]
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.[17]
The article received a flurry of criticism,[18]
but the authors later published a Cochrane
review with similar conclusions (updated as of 2010).[19]
Most studies have attributed the difference from baseline until the
end of the trial to a placebo effect, but the reviewers examined
studies which had both placebo and untreated groups in order to
distinguish the placebo effect from the natural progression of the
disease.[17]
Definitions, effects, and ethics
See also: Medical
ethics and Philosophy
of medicine
A placebo has been defined as "a substance or procedure…
that is objectively without specific activity for the condition being
treated".[18]
Under this definition, a wide variety of things can be placebos and
exhibit a placebo effect. Pharmacological
substances administered
through any means can act as placebos, including pills,
creams,
inhalants, and
injections.
Medical
devices such as ultrasound
can act as placebos.[20][21]
Sham
surgery,[22][23][24]
sham electrodes
implanted in the brain,[1]
and sham acupuncture,
either with sham needles or on fake acupuncture
points, have all exhibited placebo effects.[25]
Bedding not treated to reduce allergies
has been used as a placebo to control for treated bedding.[26]
The physician
has even been called a placebo;[27]
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".[28]
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.[29]
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 term
"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.[18]
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.[30]
The placebo effect has been controversial throughout history. Notable
medical organizations have endorsed it,[31]
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".[14]
Another possible resolution of the ethical dilemma might come from
the "honest placebo" effect found in a 2010 study[7]
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.
Although the placebo effect and theories
on its underlying mechanisms are mostly understood in terms of human
psychology, studies have also indicated that non-human animals such
as dogs can also have symptoms reduced by placebo treatments.[32]
History
Main article: Placebo
in history
A quack treating a patient with Perkins Patent Tractors by
James Gillray,
1801. John
Haygarth used this remedy to illustrate the power of the placebo
effect.
The word 'placebo', Latin for "I will please", dates back
to a Latin translation of the Bible by St
Jerome.[33]
In 1811, Hooper’s
Quincy’s Lexicon-Medicum defined placebo as "[any
medicine] adapted more to please than to benefit the
patient".[34][35]
John Haygarth
was the first to investigate the efficacy of the placebo effect in
the 18th-century.[36]
He tested a popular medical treatment of his time, called "Perkins
tractors", and showed that the remedy was ineffectual by
demonstrating that the results from a dummy remedy were just
as useful as from the alleged "active" remedy.[37]
This showed "to a degree which has never been suspected, what
powerful influence upon diseases is produced by mere
imagination".[38]
Émile
Coué, a French
pharmacist, working as an apothecary
at Troyes between
1882 and 1910, also discovered the potency of the "Placebo
Effect". He became known for reassuring his clients by praising
each remedy's efficiency and leaving a small positive notice with
each given medication. His book Self-Mastery Through Conscious
Autosuggestion was published in England (1920) and in the United
States (1922).
Placebos remained widespread in medicine until the 20th century, and
they were sometimes endorsed as necessary deceptions.[31]
In 1903, Richard
Cabot said that he was brought up to use placebos,[31]
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".[14]
In modern times, T. C. Graves first defined the "placebo effect"
in a published paper in The
Lancet in 1920.[39]
He spoke of "the placebo effects of drugs" being manifested
in those cases where "a real psychotherapeutic effect appears to
have been produced".[40]
In 1961 Henry
K. Beecher found[41]
that surgeons he categorized as enthusiasts relieved their patients'
chest pain and heart problems more than skeptic surgeons.[14]
Beginning in the 1960s, the placebo effect became widely recognized
and placebo controlled trials became the norm in the approval of new
medications.[42]
Mechanism
of the effect
Because the placebo response is simply the patient response that
cannot be attributed to an investigational intervention, there are
multiple possible components of a measured placebo effect. These
components have varying relevance depending on study design and the
types of observations.[43]
While there is some evidence that placebo interventions can alter
levels of hormones,[44]
endocannabinoids[45]
or endogenous
opioids,[46]
other prominent components include expectancy
effects, regression
to the mean,[47][48]
and flawed research methodologies.
Expectancy
and conditioning
The placebo effect is related to expectations
The placebo effect is related to the perceptions and expectations of
the patient; 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 nocebo
effect. In 1985, Irving
Kirsch hypothesized that placebo effects are produced by the
self-fulfilling effects of response expectancies, in which the belief
that one will feel different leads a person to actually feel
different.[49]
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.[50]
Both conditioning and expectations play a role in placebo effect,[51]
and make different kinds of contribution. Conditioning has a
longer-lasting effect,[52]
and can affect earlier stages of information processing.[53]
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."[54]
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.[55][56]
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.[57]
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."[58]
A placebo described as a muscle
relaxant will cause muscle relaxation and, if described as the
opposite, muscle tension.[59]
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.[60]
The perceived consumption of caffeine has been reported to cause
similar effects even when decaffeinated coffee is consumed,[61][62]
although a 2003 study found only limited support for this.[63]
Placebos represented as alcohol can cause intoxication[64]
and sensorimotor impairment.[65]
Perceived ergogenic
aids can increase endurance,[66]
speed[67]
and weight-lifting ability,[68]
leading to the question of whether placebos should be allowed in
sport competition.[69]
Placebos can help smokers quit.[70]
Perceived allergens that are not truly allergenic can cause
allergies.[71]
Interventions such as psychotherapy can have placebo effects.[72]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.[73]
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 tablets
seem to be more effective, and size can make a difference.[74]
One researcher has found that big pills increase the effect[75]
while another has argued that the effect is dependent upon cultural
background.[76]
More pills,[77]
branding,[78]
past experience,[79]
and high price[80]
increase the effect of placebo pills. Injection[81]
and acupuncture[25]
have larger effect than pills. Proper adherence
to placebos is associated with decreased mortality.[82]
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.[83][84]
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 into the placebo treatment
of gastric and duodenal ulcers shows that this varies widely with
society.[18]
The placebo effect in treating gastric ulcers is low in Brazil,
higher in northern Europe (Denmark, Netherlands), and extremely high
in Germany. However, the placebo effect in treating hypertension is
lower in Germany than elsewhere.[85]
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.[86]
The placebo effect can work selectively, under the influence of
various psychological factors. If a placebo cream is applied on one
hand with the expectation that it is an analgesic, it will reduce
pain only in that hand and not elsewhere on the body.[87]
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.[88]
Placebo
effect and the brain
Functional
imaging 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,[89][90][91]
and the spinal
cord.[92][93][94][95]
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.[53]
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).[96]
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).[97]
The rostral anterior cingulate cortex (rACC) and its subcortical
connectivity could be related to the expectation of potential pain
stimuli[98][99]
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.[90]
(It has been known that placebo analgesia depends upon the release in
the brain of endogenous
opioids since 1978.[100])
Such analgesic placebos activation changes processing lower down in
the brain by enhancing the descending inhibition through the
periaqueductal gray[90]
on spinal nociceptive
reflexes, while the expectations of anti-analgesic nocebos acts
in the opposite way to block this.[92]
The brain is also involved in less-studied ways upon nonanalgesic
placebo effects:
Parkinson's
disease: Placebo relief is associated with the release of
dopamine in the
brain.[101]
Depression:
Placebos reducing depression affect many of the same areas that are
activated by antidepressants with the addition of the prefrontal
cortex[102][103]
Caffeine:
Placebo-caffeinated coffee causes an increase in bilateral dopamine
release in the thalamus.[104]
Glucose:
The expectation of an intravenous
injection of glucose increases the release of dopamine in the basal
ganglia of men (but not women).[105]
Methylphenidate:
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.[106]
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".[107]
"Diseases lacking major 'top-down' or cortically based
regulation may be less prone to placebo-related improvement".[108]
Brain and body
For more details on this topic, see neural
top down control of physiology.
The brain has control over the body processes affected by
placebos.
In conditioning, a neutral stimulus saccharin
is paired in a drink with an agent that produces an unconditioned
response. For example, that agent might be cyclophosphamide
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.[109]
Such conditioning has been found to affect a diverse variety of not
just basic physiological processes in the immune system but ones such
as serum iron
levels, oxidative
DNA damage levels, and insulin
secretion. Recent reviews have argued the placebo effect is due to
top-down control by the brain for immunity[110]
and pain.[111]
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."[110]: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.[112]
Dopaminergic pathways have been
implicated in the placebo response in pain and depression.[113]
Evolved
health regulation
Evolutionary
medicine 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.[114]
Clinical utility
Duration
Placebo effects can last for a long time: over 8 weeks for panic
disorder,[115]
6 months for angina
pectoris,[116]
and two and half years for rheumatoid
arthritis.[117]
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.[57]
Clinical
significance
Hróbjartsson and Peter
Gøtzsche published a study in 2001[17]
and a follow-up study in 2004[118]
questioning the nature of the placebo effect. The studies were
performed as two meta-analyses.
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,[119][120]
a conclusion which Hróbjartsson & Gøtzsche
described as "powerful spin".[121]
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.[122]
Hróbjartsson and Gøtzsche's conclusion has been
criticised on several grounds. Their meta-analysis covered studies
into a highly mixed group of conditions. It has been reported that
for measurements in peripheral organs the placebo effect seems to be
more effective in achieving improvements in physical parameters (such
as decreasing hypertension, improving FEV1
in asthma sufferers, or decreasing prostatic hyperplasia or anal
fissure) than in improving biochemical parameters (such as
cholesterol or
cortisol) in
various conditions such as venous leg ulcers, Crohn's disease,
urinary tract infection, and chronic heart failure.[123]
Placebos also do not work as strongly in clinical
trials 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.[124]
Other writers have argued that the placebo effect can be reliably
demonstrated under appropriate conditions.[125]
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
intervals 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.[126]
In 2013 Jeremy
Howick et al. used Hróbjartsson & Gøtzsche's
data to compare the magnitude of placebo effects with the magnitude
of treatment effects.[127]
They found a statistically significant difference between placebo and
treatment effect sizes in trials with binary outcomes but not in
trials with subjective outcomes.
Negative effects
Similar to the placebo
effect, inert substances have the potential to cause negative effects
via the "nocebo
effect" (Latin
nocebo = "I will harm"). In this effect, giving an
inert substance has negative consequences.[128]
Another
negative consequence is that placebos can cause side-effects
associated with real treatment.[129]
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.[130]
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.[131]
Doctor-patient
relationship
A study of Danish general practitioners found that 48% had prescribed
a placebo at least 10 times in the past year.[12]
The most frequently prescribed placebos were presented as antibiotics
for viral
infections, and vitamins for fatigue. Specialists and
hospital-based physicians reported much lower rates of placebo use. A
2004 study in the British
Medical Journal of physicians in Israel found that 60% used
placebos in their medical practice, most commonly to "fend off"
requests for unjustified medications or to calm a patient.[132]
The accompanying editorial concluded, "We cannot afford to
dispense with any treatment that works, even if we are not certain
how it does."[133]
Other researchers have argued that open provision of placebos for
treating ADHD in
children can be effective in maintaining ADHD children on lower
stimulant doses in the short term.[134]
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.[135]
The following
impracticalities exist with placebos: (See the BMJ posted responses
to Spiegel's editorial rapid response online section.[133])
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.
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:
In the Committee's view, homeopathy is a placebo
treatment and the Government should have a policy on prescribing
placebos. The Government is reluctant to address the appropriateness
and ethics of prescribing placebos to patients, which usually relies
on some degree of patient deception. Prescribing of placebos is not
consistent with informed patient choice—which the Government
claims is very important—as it means patients do not have all
the information needed to make choice meaningful.
Beyond ethical
issues and the integrity of the doctor-patient relationship,
prescribing pure placebos is bad medicine. Their effect is unreliable
and unpredictable and cannot form the sole basis of any treatment on
the NHS.[15]
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.[136]
Changes over time
A review published in JAMA
Psychiatry found that, in trials of antipsychotic medications,
the change in response to receiving a placebo had increased
significantly between 1960 and 2013.[137]
The individual
Who is affected
Placebos do not work for everyone.[138][139]
Henry K.
Beecher, in a paper in 1955,[16]
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%.[139]
In research upon ischemic arm pain, placebo analgesia was found in
27%.[138]
The placebo analgesia rate for cutaneous healing of left hand skin
was 56%.[140]
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.[141]
Individual
differences
In the 1950s, there was considerable research to find whether there
was a specific personality
to those that responded to placebos. The findings could not be
replicated[142]
and it is now thought to have no effect.[143]
The desire for relief from pain, "goal motivation",
and how far pain is expected to be relieved increases placebo
analgesia.[83]
Another factor increasing the effectiveness of placebos is the degree
to which a person attends to their symptoms,
"somatic focus".[84]
Individual variation in response to analgesic placebos has been
linked to regional neurochemical differences in the internal
affective
state of the individuals experiencing pain.[144]
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.[145]
Children
seem to have greater response than adults
to placebos.[146]
Genes
In social
anxiety disorder (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.[147][148][149]
The authors note "additional work is necessary to elucidate the
generalizability of the findings".
In a 2012 study, variations on the COMT
(catechol-O-methyltransferase) gene
related to dopamine
release are found to be critical in the placebo effect among the
patients with irritable
bowel syndrome participating in the trial, a research group in
Harvard
Medical School reported. Patients with a variation of met/met,
for having two copies of the methionine
allele were shown
to be more likely to respond to the placebo treatment, while the
variation of val/val, for their two copies of valine
allele responded the least. The response of patients with one copy
each of methionine and valine fell in the middle. Release of dopamine
in patients with the met/met variations is thought to link to reward
and 'confirmation bias' which enhance the sense that the treatment is
working. The role of the COMT gene variations are expected to be more
prominent in studies where patients report more subjective conditions
such as pain and fatigue rather than objective physiological
measurements.[150][151]
Symptoms
and conditions
The placebo effect occurs more
strongly in some conditions than others. Dylan
Evans has suggested 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.[72]
Pain
The placebo
effect is believed to reduce pain in two different ways. One way is
by the placebo initiating the release of endorphins,
which are natural pain killers produced by the brain.[152]
The other way is the placebo changing the patient's perception of
pain. "A person might reinterpret a sharp pain as uncomfortable
tingling."[153]
Placebo analgesia is more likely to work the more severe the
pain.[154]
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 morphine.[141]
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%.[87]
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.[155]
The average strength of placebos upon pain on a visual
analog scale is 2 out of 10 units.[143][156]
Individuals who respond to placebos may show even greater effects, up
to 5 out of 10 units.[138]
When administered orally, placebos have
clinically meaningful effects with regard to lower
back pain.[157]
Depression
In 1998, a meta-analysis
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.[158]
A more recent meta-analysis done in 2008, analyzing data from the
FDA, revealed that 82% of the response to antidepressants was
accounted for by placebos.[159]
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.[160]
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.[161]
A 2009 meta-analysis reported that 68% of the effects of
antidepressants was due to the placebo effect.[162]
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.[58]
While
placebos seem effective, there is concern over the ethics of using
placebos as treatment for depression. While some say that blanket
consent, or the general consent to unspecified treatment given by
patients beforehand, is ethical, others argue that patients should
always obtain specific information about the name of the drug they
are receiving, its side effects, and other treatment options.[163]
Even though some patients do not want to be informed, health
professionals are ethically bound to give proper information about
the treatment given. There is such a debate over the use of placebos
because while placebos are used for the good of many to test the
effectiveness of drugs, some argue that it is unethical to ever
deprive individual patients of effective drugs.[164]
Conventionally, it is believed that placebos rely on the concept of
mind over matter and therefore are only useful if people believe that
they are receiving an actual drug.[165]
However, there is reason to believe that placebos can possibly be
effective when given without deception. As of 2012 there has only
been one study testing the efficacy of open-label placebos for
depression.[166]
In this pilot randomized control trial (RCT), patients with major
depressive disorder were either given a placebo and were informed
that they were receiving a placebo and the effectiveness of placebos,
or were put on a waitlist for treatment. There ended up being a
medium effect size or difference in response between those receiving
the placebo and those on the waitlist. While the results favored the
placebos, but were not statistically significant, the pilot study was
limited and researchers believe that openly giving placebos may have
the potential to be a valuable treatment option for depression.[167]
However, they cannot use placebos as a legitimate treatment until
further studies have been carried out and this theory has been
proven.[168]
Heath professionals will usually turn to antidepressants or
psychotherapy to treat depression.[169]
However, patients often have an aversion to taking antidepressants
because of their many side effects that are so unpleasant as to make
patients not want to take their medication at all.[170]
Therefore, psychotherapy is another good treatment option for
depression. A 2014 meta-analysis found that cognitive behavioral
therapy (CBT), a common type of psychotherapy used for treating
depression, is significantly more effective in reducing depressive
symptoms than no treatment to at all.[171]
However, combination therapy, or taking antidepressants in addition
to psychotherapy, is arguably the most effective treatment. In a
meta-analysis studying data on different treatments of depression,
combination therapy reduced depressive symptoms by over 50% and
patients taking advantage of psychotherapy or antidepressants alone,
or other treatment controls (including placebos) did not see as much
of a reduction in symptoms.[172]
Gastric
and duodenal ulcers
A meta-study of
31 placebo-controlled trials of the gastric
acid 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".[18][173]
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.[173]: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".[173]: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".[173]: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.[173]:14–15
A 1999 systematic review found that the
healing rate of duodenal ulcers was higher among groups that had
received four placebos per day, at 44.2%. This was higher than the
rate in the group that had received only two placebos per day, which
was 36.2%. The authors concluded that they "found a relation
between frequency of placebo administration and healing of duodenal
ulcer."[174]
Chronic
fatigue syndrome
It was previously
assumed that placebo response rates in patients with chronic
fatigue syndrome (CFS) are unusually high, "at least 30% to
50%", because of the subjective reporting of symptoms and the
fluctuating nature of the condition. According to a meta-analysis and
contrary to conventional wisdom, the pooled response rate in the
placebo group was 19.6%, even lower than in some other medical
conditions. The authors offer possible explanations for this result:
CFS is widely understood to be difficult to treat, which could reduce
expectations of improvement. In context of evidence showing placebos
do not have powerful clinical effects when compared to no treatment,
a low rate of spontaneous remission in CFS could contribute to
reduced improvement rates in the placebo group. Intervention type
also contributed to the heterogeneity of the response. Low patient
and provider expectations regarding psychological treatment may
explain particularly low placebo responses to psychiatric
treatments.[175]
List of
medical conditions
The effect of placebo treatments (an inert pill unless otherwise
noted) has been studied for the following medical conditions. Many of
these citations concern research showing that active treatments are
effective, but that placebo effects exist as well.
Effects on
research
Placebo-controlled
studies
Main article: Placebo-controlled
studies
The placebo effect makes it more difficult to evaluate new
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.[124]
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.[224]
Clinical trials control for this effect by including a group of
subjects that receives a sham treatment. The subjects in such trials
are blinded as to whether they receive the treatment or a placebo. If
a person is given a placebo under one name, and they respond, they
will respond in the same way on a later occasion to that placebo
under that name but not if under another.[225]
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.[124]
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.[226]
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.[227]
Nocebo
Main article: Nocebo
In the opposite
effect, a patient who disbelieves in a treatment may experience a
worsening of symptoms. This effect, now called by analogy nocebo
(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.[128]
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
oil and corn oil
in the placebo pills. However, according to the report, this "may
lead to an understatement of drug benefit: The monounsaturated and
polyunsaturated fatty acids of these 'placebos,' and their
antioxidant and anti-inflammatory effects, can reduce lipid levels
and heart disease." Another example researchers reported in the
study was a clinical trial of a new therapy for cancer patients
suffering from anorexia.
The placebo that was used included lactose.
However, since cancer patients typically face a higher risk of
lactose
intolerance, the placebo pill might actually have caused
unintended side-effects that made the experimental drug look better
in comparison.[228]
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