Placebo

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For other uses, see Placebo (disambiguation) and Placebo effect (disambiguation).
The placebo effect can be produced by inert tablets, by sham surgery, and by false information, such as when electrical stimulation is turned “off” in those with Parkinson’s disease implanted brain electrodes[1][2]
 
The placebo effect can be produced by inert tablets, by sham surgery, and by false information, such as when electrical stimulation is turned “off” in those with Parkinson’s disease implanted brain electrodes[1][2]
The placebo effect can be produced by inert tablets, by sham surgery, and by false information, such as when electrical stimulation is turned “off” in those with Parkinson’s disease implanted brain electrodes[1][2]

The placebo effect is a medical phenomenon where the results of a medical treatment are affected by the patient's ideas about how effective the treatment is. The term is especially used when a patient responds dramatically to a physiologically inactive treatment. Inactive treatments used to induce the placebo effect are called placebos; inert "sugar" pills and sham surgeries are typical examples.

The placebo effect is a pervasive phenomenon in medicine and placebos are widely used in contemporary healthcare.[3] The placebo effect sheds light on the brain's role in physical health, and allows drugs to be compared against inert equivalents in medical studies. The deceptive nature of the placebo creates tension between the Hippocratic Oath and the honesty of the doctor-patient relationship.

Contents

[edit] Placebos

[edit] Origin of the word

In the late eighteenth and early nineteenth centuries, a placebo was a term, often derogative, for the treatments doctors gave to please a patient.[4] There was no implication that it was also inert or sham.[4][5] In the middle of the twentieth century, clinical trials as to the effectiveness of medical treatments started to use control conditions in which people received inert or sham treatment, and the word “placebo” shifted to its present sense of a drug, surgery, or other medical procedure that gained its effectiveness due to the expectations of a person not its actual pharmacological or physiological action.[5] The term “placebo effect” arose also around this time.[4]

The word placebo itself originated from the Latin for I will please. It is in Latin text in the Bible (Psalm 114:1–9, Vulgate version by Jerome, “Placebo Domino in regione vivorum”, “I shall please the Lord in the land of the living”). Jerome translated as "I will please" (placebo), the Hebrew word "ethalech", "I will walk with" as in "I will be in step with".[6] This word gave its name, placebo, to the Office of the Dead church service. From that, a singer of placebo became associated with someone who falsely claimed a connection to the deceased to get a share of the funeral meal, and hence a flatterer, and so a deceptive act to please.[4]

[edit] Varieties

Placebos can be:

[edit] Placebo effect

[edit] Enhancing factors

  • Color. Red, yellow, or orange, “hot colored” tablets work better as stimulants, and “cool” colored ones--blue green, or purple--as depressants.[16]
  • Big rather than small capsules.[17]
  • Number. Two tablets are more effective than one.[18]
  • Branded proprietary tablets are more effective than unbranded ones.[19]
  • High price. Telling people they are taking a novel form of codeine (actually a placebo) that costs $2.50 rather than 10 cents increased the number of people reporting pain relief from 61% to 85.4% [20]
  • Injections have larger effect than pills.[21]
  • Devices (sham acupuncture) are more effective than inert pills.[12]
  • If an inert substance is pre-associated in past experience with a real effect.[22]
  • Placebos administered by authority figures such as shamans, general practitioners and other trusted figures may also be more powerful than when the psychological or spiritual authority figure is absent.
  • Adherence in regularly taking them (this parallels the benefits of adherence in regularly taking active treatment)[23][24]
  • The enthusiastic supportive attitude of the doctor about their effectiveness[25] In one study, the response to a placebo increased from 44% to 62% when the doctor gave them with “warmth, attention, and confidence”.[26]

[edit] Scientific theories

The phenomenon appears to defy explanation. It has been observed that "If a placebo treatment consists of an inert tablet, how is it possible for it to have any effect on the patient? The idea of a placebo effect seems illogical”.[27]

There are four scientific questions: How does the brain respond to placebos? How can the brain produce placebo effects? What about placebos causes this? And why does the brain have this capacity to produce placebo effects?

[edit] 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,[28][29][30] and the spinal cord.[31][32] 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.[33] 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).[34]

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).[35] The rostral anterior cingulate cortex and its subcortical connectivity could related to the expectation of potential pain stimuli[36][37]

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 conversely, anti-analgesic nocebos responses were associated with deactivation in this part of the brain of dopamine and opioid release.[29] (It has been known that placebo analgesia depends upon the release in the brain of endogenous opioids since 1978[38].) Such analgesic placebos activation changes processing lower down in the brain by enhancing the descending inhibition through the periaqueductal gray[29] on spinal nociceptive reflexes, while the expectations of anti-analgesic nocebos acts in the opposite way to block this.[39]

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.[40]
  • Depression: Placebos reducing depression effect many of the same areas that are activated by antidepressants with the additional of the prefrontal cortex[41][42]
  • Caffeine: placebo caffeinated coffee causes an increase in bilateral dopamine release in the thalamus.[43]
  • Glucose: the expectation of an intravenous injection of glucose increases the release of dopamine in the basal ganglia of men (but not women).[44]
  • 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.[45]

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”.[46] And “Diseases lacking major “top-down” or cortically based regulation may be less prone to placebo-related improvement”.[47]

[edit] Brain and body

For more details on this topic, see neural top down control of physiology.

The brain has control over the body processes effected by placebos. Pain, motor fatigue 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.[48] Such conditioning has been found to effect a diverse variety of basic physiological processes not just 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[49] and pain.[50] 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.”[49]pp 441

[edit] 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. The brain to do this factors in a variety of information sources, including in humans, 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.[51]

[edit] Conditioning and expectancy

Placebos could shape the brain’s top down control over the body through several processes. One is directly through a conditioning process. People can be conditioned by past experience, for example, to associate a reduction of pain with the application of a cream. The reduction in pain can be experimental arranged by surreptitiously reducing a painful stimuli after the cream is applied.[52]

Another possibility is that it also involves the learning of verbal based expectations. In this case, a person is told that a cream is analgesic but without that cream having any surreptitiously associated pain reduction. Both conditioning and verbal expectations play a role in placebo effect,[53] and make different kinds of contribution. Conditioning has a longer lasting effect,[54] and can effect earlier stages of information processing.[55] A conditioned pain reduction can totally removed when its existence is explained to them.[56]

As Irving Kirsch has noted “cognitive learning evolved from more primitive noncognitive processes. The adaptive advantage of cognition is increased response flexibility. For it to convey that benefit, however, it must be capable of overriding the influence of simpler automatic processes. Thus, the higher up the phylogenetic scale, the smaller the role of nonconscious conditioning processes and the larger the role of cognition.[57]342

[edit] Motivation and meaning

Motivation may contribute to the placebo effect. The active goals of an individual changes their somatic experience by altering the detection and interpretation of expectation-congruent symptoms, and by changing the behavioral strategies a person pursues.[58][59]

Motivation may link to the meaning through which people experience illness and treatment. Such meaning is derives 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. [60]

[edit] Expectations

The physiological effect of a placebo depends upon its suggested or anticipated action. A placebo described as a muscle relaxant will cause muscle relaxation and if the opposite, muscle tension.[61] 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.[62]

Related to this power of expectation is the person’s belief that the treatment that they are taking is real: in both those taking real drugs and those taking placebos, those people that believe they are taking the real treatment (whether they in fact are or not) show a stronger effect, and vice versa, those that think they are taking the placebo (whether they are or not) a lesser one. This effect has been found in the success of therapies as diverse as nicotine replacement therapy,[63] the transplantation of human embryonic neurons into the brains of those with advanced Parkinson's disease.[64] and acupuncture analgesia after dental treatment.[65] Those who think a treatment will work display a stronger placebo effect than those who do not, for example people sceptical about acupuncture analgesia show less placebo effect than those confident that it is a highly effective therapy.[66]

Placebo effects are strong when a treatment is adminstered overtly as this has a greater impact on a person’s expectations than the covert administration of a treatment. Pain killing and anxiety reducing drugs that are infused secretly without an individual’s knowledge are less effective (in the latter case no more so than saline) 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.[67]

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[68] 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.[69]

[edit] Awareness

A conditioned pain reduction can be totally removed when its existence is explained.[70] It has also been reported that 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.”[71] However, one classic 1965 study, despite having no control group and suffering from a sample size of only 14 individuals, suggests that patients can improve significantly by taking a placebo even when aware of the placebo condition.[72]

[edit] Culture

Placebos have greater effect in some countries than others, and this varies with condition treated. 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[73]

[edit] Clinical utility

Duration

Placebo effects can last for a long time: over 8 weeks for panic disorder,[74] 6 months for angina pectoris,[75] and two and half years for rheumatoid arthritis.[76] Placebo effects after verbal suggestion for mild pain can be robust and still exist after being repeated 10 times even if they have no actual pharmacological pain killing action[77]

[edit] Is it clinically significant?

Hróbjartsson and Peter Gøtzsche published a study in 2001[78] and a follow-up study in 2004[79] questioning the nature of the placebo effect. They performed two meta-analyses involving all published 156 clinical trials in which an experimental drug or treatment protocol was compared to a placebo group and an untreated group, and specifically asked whether the placebo group improved compared to the untreated group. Hróbjartsson and Gøtzsche 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. Similarly, 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 only be documented 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 have argued 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 ameneable to the placebo effect.[80][81].

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 chronic heart failure.[82] 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.[83] Other writers have argued that the placebo effect can be reliably demonstrated under appropriate conditions.[84]

[edit] 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.[85]

Another negative consequence is that placebos can cause side-effects associated with real treatment.[86] 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.[87]

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.[88]

[edit] Doctor-patient relationship

A study of Danish general practitioners found that 48% had prescribed a placebo at least 10 times in the past year.[3] 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 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.[89] The accompanying editorial concluded, "We cannot afford to dispense with any treatment that works, even if we are not certain how it does."[90] 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.[91]

Critics of the practice responded that it is unethical to prescribe treatments that don't work, and that telling a patient 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.
  • All placebo effects eventually wear off, thus making the placebo effect impractical for long term or chronic medical matters.
  • 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.
  • Unscrupulous medical practitioners could swindle patients with fake surgeries and sugar pills, then later claim that they only meant to help their patients by using "placebos".

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 can not 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.

[edit] The individual

[edit] Who is affected

Placebos do not work upon everyone.[92][93] Henry K. Beecher, in a paper in 1955[94] suggested placebo effects occurred to about 35% of people. However, the response rate is wide from 0% up to nearly everyone. In a dental postoperative pain model, analgesia occurred in 39%.[95] Research upon ischemic arm pain, placebo analgesia was found in 27%.[96] The analgesia for cutaneous heating of left hand skin was 56%.[97]

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.[98]

[edit] 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[99] and it now thought to have no effect.[100]

The desire for relief from pain, “goal motivation”, and how far pain is expected to be relieved increases placebo analgesia.[101] Another factor increasing the effectiveness of placebos is the degree to which a person attends to their symptoms, “somatic focus”.[102] Individual variation in response to analgesic placebos has been linked to regional neurochemical differences in the internal affective state of the individuals experiencing pain.[103]

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.[104]

Children seem to have greater response than adults to placebos.[105]

[edit] 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.[106][107][108] The authors note "additional work is necessary to elucidate the generalizability of the findings".

[edit] Symptoms and conditions

[edit] Pain

Placebo analgesia is more likely to work the more severe the pain[109] It can be effective: one study found for postoperative pain following the extraction of the third molar, that a saline injected while telling the patient it was a powerful painkiller was as potent as a 6–8 mg dose of morphine.[110]

Most research reports average reduction for a group of people, and this is 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%.[68]Another measure is the ability to endure pain. In one study, placebos increased this on average by about 3.5 minutes in the context of just under 14 minutes without it.[111] The average strength of placebos upon pain on a visual analog scale is 2 out of 10 units[112][113] Individuals that respond to placebos show greater effects and can be 5 out of 10 units.[114]

[edit] Depression

A meta-analysis in 1998 found that 75% of the effectiveness of anti-depressant medication is due to the placebo-effect rather than the treatment itself.[115] A meta-analysis in 2008 found that 79% of depressed patients receiving placebo remained well compared to 93% of those receiving antidepressants for the effect of placebos (for 12 weeks after an initial 6-8 weeks of successful therapy).[116] Another 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.[117]

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”.[118]

[edit] 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".[119] (It is now known gastic secretion is irrelevant since most ulcers are due to the the bacterium Helicobacter pylori).) 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, that 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, whilst in others the placebos were only effective in 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).

[edit] List of medical conditions

The placebo is an inert pill unless otherwise stated[120]

The placebo effect occurs more strongly with peripheral aspects of disease processes (such as hypertension, asthma, prostatic hyperplasia, anal fissure, bronchitis) rather than processes that reflect physical disease (such as venous leg ulcers, Crohn’s disease, urinary tract infection, and chronic heart failure.[172] Dylan Evans has suggested 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.[173]

[edit] List of nonmedical changes

  • Alcohol: sensorimotor performance[174]
  • Alcohol: feelings of intoxication[175]
  • Allergy lacquer tree (reaction to nonallergy leaf)[176]
  • Smoking cessation[182][63]
  • Sport doping: exercise pain and power[183]
  • Swim suits: increased speed[60] citing[184]
  • Weight lifted with leg extension: increased[185]

[edit] Placebo-controlled studies

Main article: 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[citation needed]. 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. Often clinical trials are double blinded so that the researchers also do not know which 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.[186]

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 violates the rights of that person to receive the best available treatment. This issue is covered by the Declaration of Helsinki.

[edit] History

Kaptchuk[5] has shown that both the name and the concept of placebo were transferred from at least 200 years of use in clinical practice, in the decade following the second world war, to a new role required by the methodology of what was then the new discipline of 'clinical research'. Earlier usage corresponded to its Latin etymology – a harmless pill or potion given knowingly to patients who were either hard to please or hard to cure. The first clear example cited in the OED is from 1811. But during the post-war therapeutic revolution, it became the trashcan into which all the confounding factors that disturb therapeutic assessments were tipped. In Beecher's terms, it became a powerful if enigmatic distraction to researchers, whose results would be contaminated without rigorous procedures for its exclusion. Its modern use is therefore quite recent, and closely related to the adoption of the RCT as the methodological gold standard for trials of therapy.

[edit] Earlier usage

Hooper’s (1811) Quincy’s Lexicon-Medicum defines placebo as "an epithet given to any medicine adapted more to please than benefit the patient".

In the practice of medicine it had been long understood that, as Ambroise Paré (1510–1590) had expressed it, the physician’s duty was to "cure occasionally, relieve often, console always" ("Guérir quelquefois, soulager souvent, consoler toujours").

According to Jewson, eighteenth century English medicine was gradually moving away from the patient having a considerable interaction with the physician—and, through this consultative relationship, having an equal influence on the construction of the physician’s therapeutic approach—and it was gradually moving towards that of the patient being the recipient of a far more standard form of intervention that was determined by the prevailing opinions of the medical profession of the day. (Jewson 1974; Jewson 1976)

Jewson characterizes this as parallel to the changes that were taking place in the manner in which medical knowledge was being produced; namely, a transition all the way from "bedside medicine", through "hospital medicine", to "laboratory medicine" (Jewson 1976, p.227) (for more on the effect of the development of various types of medical technology see Medical sign#Increased reliance on signs).

From this point of view, the last vestiges of the "consoling" approach to treatment are to be found in the administration – often without any sort of adequate history being taken or any sort of appropriate physical examination being made (Carter 1953, p.823) – of the morale-boosting and pleasing remedies, such as the "sugar pill", electuary or pharmaceutical syrup; all of which had no known pharmacodynamic action.

Those doctors who provided their patients with these sorts of morale-boosting therapies (which, whilst having no pharmacologically active ingredients, provided reassurance and comfort) did so either to reassure their patients whilst the Vis medicatrix naturae (i.e., "the healing power of nature") performed its normalizing task of restoring them to health, or to gratify their patients’ need for an active treatment.

Some statements about the role of placebos in doctor patient relationship are:

  • Cooper (1823, p.259): "[When applying] the compound decoction of the sarsaparilla … [in cases of] irritable ulcer, … some think it placebo; others have a very high opinion of its efficacy … [when it is used] after the use of mercury, it diminishes the irritability of the constitution, and soon soothes the system into peace".
  • Shapiro[4]p.656: "[This use of the term "placebo" is a form of] positioning … Introduction of the word placebo to describe a class of treatments not previously specified was an important development in the history of methodology and medicine."
  • Handfield-Jones (1953): "some patients are so unintelligent, neurotic, or inadequate as to be incurable, and life is made easier for them by placebo".
  • Platt (1947, p.307): "the frequency with which placebos are used varies inversely with the combined intellligence [sic] of the doctor and his patient".
  • Steele (1891, pp 277–278)"To argue with a man, and especially with a woman, that there is little the matter with them might be thought injudicious, and to advise them to return at a more convenient occasion requires more time and resolution than writing out a prescription or administering a placebo."
  • But Shapiro[4]p.679: "If a placebo is prescribed by a physician because it is thought that it will help the patient, then it is a specific [remedy] and therefore not a placebo [at all]."
  • An editorial in the British Medical Journal of 19 January 1952 (p.150): "But it is a fallacy to suppose that an inactive medicine can do no harm. If prescribed in a perfunctory way for a patient needing explanation and reassurance it may increase faith in his disease rather than in the remedy, and a doctor who gives a placebo in the wrong spirit may harm the patient."
  • Pepper (1945, p.411): "There may be a time when during the carrying out of diagnostic tests it is undesirable to give potent medicine lest it interfere with the tests and yet the patient must be encouraged by treatment. … there is a certain amount of skill in the choice and administration of a placebo. In the first place, it must be nothing more than what the name implies a medicine without any pharmacologic action whatever. Even a mild sedative is not a true placebo. Secondly, its name must be unknown to even the most inveterate patient who knows most drugs by name and is always quick to read the prescription. If the medicines named are familiar, the type of patient who needs a placebo will promptly exclaim that this or that drug had been tried and "had not helped me" or "had upset my stomach". It is well if the drug have a Latin and polysyllabic name; it is wise if it be prescribed with some assurance and emphasis for psychotherapeutic effect. The older physicians each had his favorite placeboic prescriptions—one chose Tincture of Condurango, another the Fluidextract [sic] of Cimicifuga nigra. Certainly this latter by its Latin name might be expected to have more supratentorial action than if one merely wrote for the Black Cohosh, and Condurango would be more effectual than sugar of milk." Pepper's assertion that a placebo "must be nothing more than what the name implies"—namely that it must be "a medicine without any pharmacologic action whatever"—in order for it to be called a placebo, is most significant.
  • Findley (1953), p.1826 & p.1824: "[If the placebo is not] used as an instrument of deception, but as a technique for cementing the emotional bond which must attach doctor to patient if any form of treatment is to be really successful… [it was] the most important weapon the physician has … [specifically because] in proportion as this [doctor-patient] bond is firm, the [patient's] need for drugs will likely diminish."
  • Leslie (1954, p.854): "Because medicine has been so concerned with its scientific growth, too little attention has been paid to advancing the art of medicine, to which therapy with placebos belongs, and consequently knowledge of the use of placebos has not progressed significantly."
  • Carruthers, Hoffman, Melmon & Nierenberg (2000, p.1268): "In clinical practice, where a majority of patient visits are for conditions that cannot be explained on a pathophysiologic basis of for which no specific treatment is available, it is essential that physicians understand the concepts and principles of placebos and placebo effects and, when appropriate, use them correctly".

[edit] "Placebo effect"

Graves was possibly the first to mention the "placebo effect", when he spoke in 1920 of "the placebo effects of drugs" being manifested in those cases where "a real psychotherapeutic effect appears to have been produced". (Graves 1920, p.1135)

In the 1930s Evans and Hoyle (1933), (using 90 subjects), and Gold, Kwit and Otto (1937), (using 700 subjects), published studies which compared the outcomes from the administration of an active drug and a dummy simulator (which both research groups called a "placebo") in the same trial. Neither experiment displayed any significant difference between drug treatment and placebo treatment;[citation needed] leading the researchers to conclude that the drug exerted no specific effects in relation to the conditions being treated.

In 1946, the Yale biostatistician and physiologist E. Morton Jellinek was the first to mention either a "placebo reaction" or a "placebo response". He spoke of a "response to placebo" (p.88), those who "responded to placebo" (p.88), a "reaction to placebo" (p.89), and of "reactors to placebo" (p.90). This suggests that to Jellinek the terms "placebo response" and "placebo reaction"—or the terms "placebo responder" and "placebo reactor"—were identical and interchangeable.

General literature attributes the term "placebo effect" to Henry K. Beecher's 1955 paper The Powerful Placebo, where, however, he only speaks of placebo effects when he is contrasting them with drug effects. Otherwise, he always speaks of "placebo reactors" and "placebo non-reactors". Beecher (1952), Beecher et al. (1953), Beecher (1959), consistently speak of "placebo reactors" and "placebo non-reactors"; they never speak of any "placebo effect". Beecher (1970) simply speaks of "placebos".

The word obecalp, "placebo" spelled backwards was coined by an Australian doctor in 1998 when he recognised the need for a freely available placebo.[187] The word is sometimes used to make the use or prescription of fake medicine less obvious to the patient.[188]

It has been suggested that a distinction exists between the placebo effect (which applies to a group) and the placebo response (which is individual).[189]

[edit] 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 the "nocebo effect" (Latin nocebo = "I will 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.[190]

[edit] See also

Sister project Look up placebo in
Wiktionary, the free dictionary.

[edit] References

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  158. ^ Hoffman GA, Harrington A, Fields HL. (2005) Pain and the placebo: what we have learned. Perspect Biol Med. 48:248-65.PubMed
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  188. ^ E.g. see Gulf War Veteran Gets Placebos Instead Of Real Medicine or BehindTheMedspeak: Obecalp.
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  190. ^ The Nocebo Effect

[edit] Books

  • Bausell, R. Barker (2007), Snake Oil Science: The Truth About Complementary and Alternative Medicine, Oxford University Press, ISBN 978-0-19-531368-0  Has several chapters on the placebo effect.
  • Beecher, H.K., Measurement of Subjective Responses: Quantitative Effects of Drugs, Oxford University Press, (New York), 1959.
  • Beecher, H.K., Research and the Individual: Human Studies, Little, Brown, (Boston), 1970. [ISBN 0-7000-0168-9]
  • Bernheim, H. (trans. by Herter C.A. from Second, revised French Edition of 1887), Suggestive Therapeutics: A Treatise on the Nature and Uses of Hypnotism, G.P. Putnam's Sons, (New York), 1889.
  • Brody, Howard (1980). Placebos and the Philosophy of Medicine: Clinical, Conceptual, and Ethical Issues. University of Chicago Press. ISBN 978-0226075310. 
  • Brody, Howard (2000). The Placebo response. New York: Harper Collins Publishers. ISBN 0-06-019493-6. 
  • Carruthers, S.G., Hoffman, B.B., Melmon, K.L. & Nierenberg, D.W. (eds.), Melmon and Morrelli's Clinical Pharmacology: Basic Principles in Therapeutics (Fourth Edition), McGraw-Hill, (London), 2000.
  • Evans, Dylan 2004. Placebo: Mind over Matter in Modern Medicine. HarperCollins (UK) / Oxford University Press (US). ISBN 978-0007126132 / ISBN 978-0195220544.
  • Gauld, A., A History of Hypnotism, Cambridge University Press, (Cambridge), 1992.
  • Guess, Harry; Engel, Linda; Kleinman, Arthur; Kusek, John (editors) (2002). Science of the Placebo: Toward an Interdisciplinanary Research Agenda. BMJ Books. ISBN 978-0727915948. 
  • Harrington, Anne, ed. 1997. The Placebo Effect: An Interdisciplinary Exploration. Cambridge: Harvard University Press. ISBN 067466986X
  • Haygarth, J., Of the Imagination, as a Cause and as a Cure of Disorders of the Body; Exemplified by Fictitious Tractors, and Epidemical Convulsions (New Edition, with Additional Remarks), Crutwell, (Bath), 1801.
  • Moerman, Daniel E. (2002). Meaning, Medicine and the 'Placebo Effect'. Cambridge University Press. 
  • Senn SJ. 2003. Dicing with Death: Chance, Risk and Health (Cambridge University Press: Cambridge, UK. ISBN 0-521-54023-2.
  • Wilson, I., The Bleeding Mind: An Investigation into the Mysterious Phenomenon of Stigmata, Paladin, (London), 1991.

[edit] History of medicine

  • Anonymous, "The Bottle of Medicine" [Editorial], British Medical Journal, No.4750, (19 January 1952), pp.149–150. Estimates that 40% of general practice patients receive a bottle of medicine as a placebo.
  • Ayad, H., "Khellin in Angina Pectoris", The Lancet, Vol.251, No.6495, (21 February 1948), Page 305.
  • Cooper, A., "Surgical Lectures", The Lancet, Vol.1, No.8, (23 November 1823), pp.253–260.
  • Diehl, H.S., Baker, A.B. & Cowan, D.W., " Cold Vaccines: An Evaluation Based on a Controlled Study", Journal of the American Medical Association, Vol.111, No.13, (24 September 1938), pp.1168–1173.
  • Dunn, Peter M. (1997). "James Lind (1716-94) of Edinburgh and the treatment of scurvy". Archives of Disease in Childhood Fetal & Neonatal Edition 76: F64–5. PMID 9059193. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=9059193. 
  • Evans, W. & Hoyle, C., "The Comparative Value of Drugs Used in the Continuous Treatment of Angina Pectoris", Quarterly Journal of Medicine, No.7 (Vol.2, No.4), (July 1933), pp.311–338.
  • Flexner, A., Medical Education in the United States and Canada: A Report to the Carnegie Foundation for the Advancement of Teaching (Bulletin Number Four), The Merrymont Press, (Boston), 1910. [1]
  • Flint, A., "A Contribution Toward the Natural History of Articular Rheumatism, Consisting of a Report of Thirteen Cases Treated Solely with Palliative Measures", American Journal of Medical Science, Vol.46, (July 1863), pp.17–36.
  • Gold, H., Kwit, N.T. & Otto H., "The Xanthines (Theobromine and Aminophyllin) in the Treatment of Cardiac Pain", Journal of the American Medical Association, Vol.108, No.26, (26 June 1937), pp.2173–2179.
  • Graves, T.C., "Commentary on a Case of Hystero-Epilepsy with Delayed Puberty: Treated with Testicular Extract", The Lancet, Vol.196, No.5075, (4 December 1920), pp.1134–1135.
  • Handfield-Jones, R.P.C., "A Bottle of Medicine from the Doctor", The Lancet, Vol.262, No.6790, (17 October 1953), pp.823–825.
  • Jellinek, E. M. "Clinical Tests on Comparative Effectiveness of Analgesic Drugs", Biometrics Bulletin, Vol.2, No.5, (October 1946), pp.87–91.
  • Pepper, O.H.P., "A Note on the Placebo", American Journal of Pharmacy, Vol.117, (November 1945), pp.409–412.
  • Platt, R., "Two Essays on the Practice of Medicine", The Lancet, Vol.250, No.6470, (30 August 1947), pp.305–307.
  • Steele, Dr., "The Charitable Aspects of Medical Relief", Journal of the Royal Statistical Society, Vol.54, No.2, (June 1891), pp.263–310.
  • Wolf, S., "Effects of Suggestion and Conditioning on the Action of Chemical Agents in Human Subjects; The Pharmacology of Placebos", Journal of Clinical Investigation, Vol.29, No.1, (January 1950), pp.100–109.

[edit] Modern research

  • Barfod TS. 2005. Placebos in medicine: placebo use is well known, placebo effect is not. BMJ. 330:45. PMID 15626817.
  • Beecher, H.K., "Experimental Pharmacology and Measurement of the Subjective Response", Science, Vol.116, No.3007, (15 August 1952), pp.157–162.
  • Beecher, H. K. 1955. "The powerful placebo". Journal of the American Medical Association, 159:1602–1606. PMID 13271123. Original article describing a widespread placebo effect.
  • Beecher, H.K., Keats, A.S., Mosteller, F. & Lasagna, L., "The Effectiveness of Oral Analgesics (Morphine, Codeine, Acetylsalicylic Acid) and the Problem of Placebo "Reactors" and "Non-Reactors"", Journal of Pharmacology and Experimental Therapeutics, Vol.109, No.4, (December 1953), pp.393–400.
  • Benedetti, Fabrizio; Mayberg, Helen S.; Wager, Tor D.;. Stohler, Christian S.; Zubieta, Jon-Kar (2005). "Neurobiological mechanisms of the placebo effect". Journal of Neuroscience 25: 10390–402. doi:10.1523/JNEUROSCI.3458-05.2005. PMID 16280578. 
  • Benedetti, Fabrizio; Pollo, Antonella; Lopiano, Leonardo; Lanotte, Michelle; Vighetti, Sergio; Rainero, Innocenzo (2003). "Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses". Journal of Neuroscience 23: 4315–23. PMID 12764120. 
  • Benson, Herbert; Friedman, Richard (1996). "Harnessing the power of the placebo effect and renaming it "remembered wellness"". Annual Review of Medicine 47: 193–9. doi:10.1146/annurev.med.47.1.193. 
  • Carter, A.B., "The Placebo: Its Use and Abuse", The Lancet, Vol.262, No.6790, (17 October 1953), p.823.
  • Chambless, D.L. & Hollon, S.D., "Defining Empirically Supported Therapies", Journal of Consulting and Clinical Psychology, Vol.66, No.1, (February 1998), pp.7–18.
  • Coronary Drug Project (1980). "Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project". New England Journal of Medicine 303: 1038–41. 
  • Di Blasi Z, Reilly D. 2005. Placebos in medicine: medical paradoxes need disentangling. BMJ. 330:45. PMID 15626818.
  • Evans D. 2005. Suppression of the acute-phase response as a biological mechanism for the placebo effect. Med Hypotheses. 64:1–7. PMID 15533601.
  • Findley, T., "The Placebo and the Physician", Medical Clinics of North America, Vol.37, (November 1953), pp.1821–1826.
  • Finniss, Damien G.; Benedetti, Fabrizio (2005). "Mechanisms of the placebo response and their impact on clinical trials and clinical practice". Pain 114: 3–6. doi:10.1016/j.pain.2004.12.012. 
  • Gaddum, F.M., "Walter Ernest Dixon Memorial Lecture: Clinical Pharmacology", Proceedings of the Royal Society of Medicine, Vol.47, No.3, (March 1954), pp.195–204.
  • Gallagher, E. J.; Viscoli, C. M.; Horwitz, R. I. (1993). "The relationship of treatment adherence to the risk of death after myocardial infarction in women". Journal of the American Medical Association 270: 742–4. doi:10.1001/jama.270.6.742. PMID 8336377. 
  • Geers AL et al. 2005. Goal activation, expectations, and the placebo effect. J Pers Soc Psychol. 89:143–159. PMID 16162050.
  • Green, S.A., "The Origins of Modern Clinical Research", Clinical Orthopaedics and Related Research, Vol.405, (December 2002), pp.311–319.
  • Harman, W.W., McKim, R.H., Mogar, R.E., Fadiman, J. & Stolaroff, M.J., "Psychedelic Agents in Creative Problem-Solving: A Pilot Study, Psychological Reports, Vol.19, No.1, (August 1966), pp.211–227.
  • Herbert, James D.; Gaudiano, Brandon A. (2005). "Introduction to the special issue on the placebo concept in psychotherapy". Journal of Clinical Psychology 61: 787–90. doi:10.1002/jclp.20125. 
  • Hyland, M. E. (2003). Using the placebo response in clinical practice. Clinical Medicine (London, England), 3, 347–350.
  • Jewson, N.D., "Medical Knowledge and the Patronage System in 18th Century England", Sociology, Vol.8, No.3, (1974), pp.369–385.
  • Jewson, N.D., "The Disappearance of the Sick Man from Medical Cosmology, 1770–1870", Sociology, Vol.10, No.2, (1976), pp.225–244.
  • Kaptchuk, Ted J. (1998a). "Intentional ignorance: A history of blind assessment and placebo controls in medicine". Bulletin of the History of Medicine 72: 389–433. doi:10.1353/bhm.1998.0159. 
  • Kaptchuk, Ted J. (1998b). "Powerful placebo: the dark side of the randomised controlled trial". Lancet 351: 1722–5. doi:10.1016/S0140-6736(97)10111-8. 
  • Khan A, Warner HA, and Brown WA. 2000. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: an analysis of the Food and Drug Administration database. Arch Gen Psychiatry 57:311–317. PMID 10768687
  • Kienle, Gunver S.; Kiene, Helmut (1997). "The Powerful Placebo Effect: Fact or Fiction?". Journal of Clinical Epidemiology 50: 1311–8. doi:10.1016/S0895-4356(97)00203-5.  Challenges (Beecher 1955).
  • Kleijnen, J.; de Craen AJ, van Everdingen J, Krol L. (1994). "Placebo effect in double-blind clinical trials: a review of interactions with medications". Lancet 344: 1347–9. doi:10.1016/S0140-6736(94)90699-8. 
  • Lasagna, L., Mosteller, F., von Felsinger, J.M. & Beecher, H.K., "A Study of the Placebo Response", American Journal of Medicine, Vol.16, No.6, (June 1954), pp.770–779.
  • Leuchter AF, Cook IA et al (2002). Changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry. 159:122–129. PMID 11772700.
  • Leslie, A., "Ethics and Practice of Placebo Therapy", American Journal of Medicine, Vol.16, No.6, (June 1954), pp.854–862.
  • Lohr, J.M., Olatunji, B.O., Parker, L. & DeMaio, C., "Experimental Analysis of Specific Treatment Factors: Efficacy and Practice Implications", Journal of Clinical Psychology, Vol.61, No.7, (July 2005), pp.819–834.
  • McClure, Samuel M.; Li Jian; Tomlin, Damon; Cypert, Kim S.; Montague, Latané M.; Montague, P. Read (2004). "Neural Correlates of Behavioral Preference for Culturally Familiar Drinks". Neuron 44: 379–87. doi:10.1016/j.neuron.2004.09.019. 
  • Margo CE. 1999. The placebo effect. Surv Ophthalmol. 44:31–44. PMID 10466586.
  • Moerman, Daniel E. (1983). "General Medical Effectiveness and Human Biology: Placebo effects in the treatment of ulcer disease". Medical Anthropology Quarterly 14: 3–16. doi:10.1525/maq.1983.14.4.02a00020. 
  • NIH State-of-the-Science Panel (2005). "National Institutes of Health State-of-the-Science Conference statement: management of menopause-related symptoms". Annals of Internal Medicine 142 (12 Part 1): 1003–13. PMID 15968015. http://www.annals.org/cgi/content/full/142/12_Part_1/1003. 
  • Nitzan U, Lichtenberg P. 2004. Questionnaire survey on use of placebo. BMJ 329:944–946. PMID 15377572.
  • Ockene, JK; Barad, D. H.; Cochrane, B. B.; Larson, J. C.; Gass, M.; Wassertheil-Smoller, S.; Manson, J. E.; Barnabei, V. M.; Lane, D. S.; Brzyski, R. G.; Rosal, M. C.; Wylie-Rosett, J.; Hays, J. (2005). "Symptom experience after discontinuing use of estrogen plus progestin". Journal of the American Medical Association 294 (2): 183–193. doi:10.1001/jama.294.2.183. PMID 16014592. http://jama.ama-assn.org/cgi/content/full/294/2/183. 
  • Perlman, L, "Nonspecific, Unintended, and Serendipitous Effects in Psychotherapy", Professional Psychology: Research and Practice, Vol.32, No.3, (June 2001), pp.283–288.
  • Ploghaus, Alexander; Becerra, Lino; Borras, Cristina; Borsook, David (2003). "Neural circuitry underlying pain modulation: expectation, hypnosis, placebo". Trends in Cognitive Sciences 7: 197–200. doi:10.1016/S1364-6613(03)00061-5. 
  • Price DD et al. 1999. An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain. 83:147–156. PMID 10534585.
  • Ross, Sherman; Krugman, Arnold D.; Lyerly, Samuel B.; Clyde, Dean J (1962). "Drugs and placebos: A model design". Psychological Reports 10: 383–92. doi:10.2466/PR0.10.2.383-392. 
  • Sauro MD. 2005. Endogenous opiates and the placebo effect: a meta-analytic review. J Psychosom Res. 58:115–120. PMID 15820838.
  • Shapiro, A.K., "Semantics of the Placebo", Psychiatric Quarterly, Vol.42, No.4, (December 1968), pp.653–695.
  • Spiegel D. 2004. Placebos in practice. BMJ. 329:927–928. PMID 15499085.
  • Wager TD, Rilling JK, Smith EE et al. 2004. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science. 303:1162–1167. PMID 14976306
  • Zubieta JK, Bueller JA et al. 2005. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci. 25:7754–7762. PMID 16120776.

[edit] General audience

[edit] External links

Retrieved from "http://en.wikipedia.org/wiki/Placebo"
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