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A placebo ( ) can be roughly defined as a medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
Placebos are used in randomized clinical trials to test the efficacy of Drug. In a placebo-controlled trial, any change in the control group is known as the placebo response, and the difference between this and the result of no treatment is the placebo effect. Placebos in clinical trials should ideally be indistinguishable from so-called verum treatments under investigation, except for the latter's particular hypothesized medicinal effect. This is to shield test participants (with their consent) from knowing who is getting the placebo and who is getting the treatment under test, as patients' and clinicians' expectations of efficacy can influence results.
The idea of a placebo effect was discussed in 18th century psychology,Schwarz, K. A., & Pfister, R.: Scientific psychology in the 18th century: a historical rediscovery. In: Perspectives on Psychological Science, Nr. 11, pp. 399–407. but became more prominent in the 20th century. Modern studies find that placebos can affect some outcomes such as pain and nausea, but otherwise do not generally have important clinical effects. Improvements that patients experience after being treated with a placebo can also be due to unrelated factors, such as regression to the mean (a statistical effect where an unusually high or low measurement is likely to be followed by a less extreme one). The use of placebos in clinical medicine raises ethical concerns, especially if they are disguised as an active treatment, as this introduces dishonesty into the doctor–patient relationship and bypasses informed consent.
Placebos are also popular because they can sometimes produce relief through psychological mechanisms (a phenomenon known as the "placebo effect"). They can affect how patients perceive their condition and encourage the body's chemical processes for relieving pain and a few other symptoms, but have no impact on the disease itself.
The definition of placebo has been debated. One definition states that a treatment process is a placebo when none of the characteristic treatment factors are effective (remedial or harmful) in the patient for a given disease.
In a clinical trial, a placebo response is the measured response of subjects to a placebo; the placebo effect is the difference between that response and no treatment. The placebo response may include improvements due to natural healing, declines due to natural disease progression, the tendency for people who were temporarily feeling either better or worse than usual to return to their average situations (regression toward the mean), and errors in the clinical trial records, which can make it appear that a change has happened when nothing has changed. It is also part of the recorded response to any active medical intervention.
Measurable placebo effects may be either objective (e.g. lowered blood pressure) or subjective (e.g. a lowered perception of pain).
Measuring the extent of the placebo effect is difficult due to confounding factors. Gøtzsche's biographical article has further references related to this work. For example, a patient may feel better after taking a placebo due to regression to the mean (i.e. a natural recovery or change in symptoms), but this can be ruled out by comparing the placebo group with a no treatment group (as all the placebo research does). It is harder still to tell the difference between the placebo effect and the effects of response bias, observer bias and other flaws in trial methodology, as a trial comparing placebo treatment and no treatment will not be a blinded experiment. In their 2010 meta-analysis of the placebo effect, Asbjørn Hróbjartsson and Peter C. Gøtzsche argue that "even if there were no true effect of placebo, one would expect to record differences between placebo and no-treatment groups due to bias associated with lack of blinding".
One way in which the magnitude of placebo analgesia can be measured is by conducting "open/hidden" studies, in which some patients receive an analgesic and are informed that they will be receiving it (open), while others are administered the same drug without their knowledge (hidden). Such studies have found that analgesics are considerably more effective when the patient knows they are receiving them.
Individual differences in personality traits may influence susceptibility to placebo and nocebo (negative placebo) effects. People with a more optimistic outlook tend to exhibit stronger placebo responses, while those with higher levels of anxiety are more likely to experience nocebo effects.
childhood seem to have a greater response than adults to placebos.
The administration of the placebos can determine the placebo effect strength. Studies have found that taking more pills would strengthen the effect. Capsules appear to be more influential than pills, and injections are even stronger than capsules.
Some studies have investigated the use of placebos where the patient is fully aware that the treatment is inert, known as an Open-label trial. Clinical trials found that open-label placebos may have positive effects in comparison to no treatment, which may open new avenues for treatments, but a review of such trials noted that they were done with a small number of participants and hence should be interpreted with "caution" until further, better-controlled trials are conducted. An updated 2021 systematic review and meta-analysis based on 11 studies also found a significant, albeit slightly smaller overall effect of open-label placebos, while noting that "research on OLPs is still in its infancy".
If the person dispensing the placebo shows their care towards the patient, is friendly and sympathetic, or has a high expectation of a treatment's success, then the placebo is more effectual.
Another meta-analysis found that 79% of depressed patients receiving placebo remained well (for 12 weeks after an initial 6–8 weeks of successful therapy) compared to 93% of those receiving antidepressants. In the continuation phase however, patients on placebo relapsed significantly more often than patients on antidepressants.
Another negative consequence is that placebos can cause side-effects associated with real treatment.
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 Drug withdrawal symptoms were reported by 4.8% of those on placebo compared to 21.3% of those on hormone replacement.
The ethics of placebo-controlled studies have been debated in the revision process of the Declaration of Helsinki. Of particular concern has been the difference between trials comparing inert placebos with experimental treatments, versus comparing the best available treatment with an experimental treatment; and differences between trials in the sponsor's developed countries versus the trial's targeted developing countries.
Some suggest that existing medical treatments should be used instead of placebos, to avoid having some patients not receive medicine during the trial.
Despite the abovementioned issues, 60% of surveyed physicians and head nurses reported using placebos in an Israeli study, with only 5% of respondents stating that placebo use should be strictly prohibited. A 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." 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. Doctors Struggle With Tougher-Than-Ever Dilemmas: Other Ethical Issues Author: Leslie Kane. 11/11/2010
Referring specifically to homeopathy, the House of Commons of the United Kingdom Science and Technology Committee has stated:
In his 2008 book Bad Science, Ben Goldacre argues that instead of deceiving patients with placebos, doctors should use the placebo effect to enhance effective medicines.
Edzard Ernst has argued similarly that "As a good doctor you should be able to transmit a placebo effect through the compassion you show your patients." In an opinion piece about homeopathy, Ernst argues that it is wrong to support alternative medicine on the basis that it can make patients feel better through the placebo effect. His concerns are that it is deceitful and that the placebo effect is unreliable. Goldacre also concludes that the placebo effect does not justify alternative medicine, arguing that unscientific medicine could lead to patients not receiving prevention advice. Placebo researcher Fabrizio Benedetti also expresses concern over the potential for placebos to be used unethically, warning that there is an increase in "quackery" and that an "alternative industry that preys on the vulnerable" is developing.
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. 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. Similarly, the appearance of effect can result from classical conditioning, wherein a placebo and an actual stimulus are used simultaneously until the placebo is associated with the effect from the actual stimulus. Both conditioning and expectations play a role in placebo effect, and make different kinds of contributions. Conditioning has a longer-lasting effect, and can affect earlier stages of information processing. Those who think a treatment will work display a stronger placebo effect than those who do not, as evidenced by a study of acupuncture.
Additionally, motivation may contribute to the placebo effect. The active goals of an individual changes their somatic experience by altering the detection and interpretation of expectation-congruent symptoms, and by changing the behavioral strategies a person pursues. 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.
Since 1978, it has been known that placebo analgesia depends upon the release of endogenous opioids in the brain. Such analgesic placebos activation changes processing lower down in the brain by enhancing the descending inhibition through the periaqueductal gray on spinal nociceptive reflexes, while the expectations of anti-analgesic nocebos acts in the opposite way to block this.
Functional imaging upon placebo analgesia has been summarized as showing that the placebo response is "mediated by 'top-down' processes dependent on frontal cortical areas that generate and maintain cognitive expectancies. Dopaminergic reward pathways may underlie these expectancies". "Diseases lacking major 'top-down' or cortically based regulation may be less prone to placebo-related improvement".
Dopaminergic pathways have been implicated in the placebo response in pain and depression.
It was recognized in the 18th and 19th centuries that drugs or remedies often were perceived to work best while they were still novel:Arthur K. Shapiro, Elaine Shapiro, The Powerful Placebo: From Ancient Priest to Modern Physician, 2006, , chapter "The Placebo Effect in Medical History"
Placebos have featured in medical use until well into the twentieth century. An influential 1955 study entitled The Powerful Placebo firmly established the idea that placebo effects were clinically important, and were a result of the brain's role in physical health. A 1997 reassessment found no evidence of any placebo effect in the source data, as the study had not accounted for regression to the mean.Stoddart, Charlotte, How placebo effect went mainstream, Knowable Magazine, June 27, 2023
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.
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