Placebo
A placebo can be roughly defined as a sham medical treatment. Common placebos include inert tablets, inert injections, sham surgery, and other procedures.
Placebos are used in randomized clinical trials to test the efficacy of medical treatments. 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 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, 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. 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. 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.
Etymology and definition
The Latin term placebo means shall be pleasing.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 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, 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 or subjective.
Effects
The placebo effect is a well-documented phenomenon, though it remains widely misunderstood and surrounded by misconceptions. Several studies have questioned its clinical relevance, fueling ongoing debate about its actual effectiveness. A 2001 meta-analysis of the placebo effect looked at trials in 40 different medical conditions, and concluded the only one where it had been shown to have a significant effect was for pain. Another Cochrane review in 2010 suggested that placebo effects are apparent only in subjective, continuous measures, and in the treatment of pain and related conditions. The review found that placebos do not appear to affect the actual diseases, or outcomes that are not dependent on a patient's perception. The authors, Asbjørn Hróbjartsson and Peter C. Gøtzsche, concluded that their study "did not find that placebo interventions have important clinical effects in general." This interpretation has been subject to criticism, particularly due to concerns about the adequacy of the methodology used. Recent research has linked placebo interventions to improved motor functions in patients with Parkinson's disease. Other objective outcomes affected by placebos include immune and endocrine parameters, end-organ functions regulated by the autonomic nervous system, and sport performance.Measuring the extent of the placebo effect is difficult due to confounding factors. For example, a patient may feel better after taking a placebo due to regression to the mean, but this can be ruled out by comparing the placebo group with a no treatment group. 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, while others are administered the same drug without their knowledge. Such studies have found that analgesics are considerably more effective when the patient knows they are receiving them.
Factors influencing the power of the placebo effect
A review published in JAMA Psychiatry found that, in trials of antipsychotic medications, the change in response to receiving a placebo had increased significantly between 1960 and 2013. The review's authors identified several factors that could be responsible for this change, including inflation of baseline scores and enrollment of fewer severely ill patients. Another analysis published in Pain in 2015 found that placebo responses had increased considerably in neuropathic pain clinical trials conducted in the United States from 1990 to 2013. The researchers suggested that this may be because such trials have "increased in study size and length" during this time period.Individual differences in personality traits may influence susceptibility to placebo and nocebo 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.
Children 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 placebo. 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.
Depression
In 2008, a meta-analysis led by psychologist Irving Kirsch, analyzing data from the Food and Drug Administration, concluded that 82% of the response to antidepressants was accounted for by placebos. However, other authors expressed doubts about the used methods and the interpretation of the results, especially the use of 0.5 as the cut-off point for the effect size. A complete reanalysis and recalculation based on the same FDA data found that the Kirsch study had "important flaws in the calculations." The authors concluded that although a large percentage of the placebo response was due to expectancy, this was not true for the active drug. Besides confirming drug effectiveness, they found that the drug effect was not related to depression severity.Another meta-analysis found that 79% of depressed patients receiving placebo remained well compared to 93% of those receiving antidepressants. In the continuation phase however, patients on placebo relapsed significantly more often than patients on antidepressants.
Negative effects
A phenomenon opposite to the placebo effect has also been observed. When an inactive substance or treatment is administered to a recipient who has an expectation of it having a negative impact, this intervention is known as a nocebo. A nocebo effect occurs when the recipient of an inert substance reports a negative effect or a worsening of symptoms, with the outcome resulting not from the substance itself, but from negative expectations about the treatment.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 withdrawal symptoms were reported by 4.8% of those on placebo compared to 21.3% of those on hormone replacement.
Ethics
In research trials
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 treatment. Informed consent is usually required for a study to be considered ethical, including the disclosure that some test subjects will receive placebo treatments.The ethics of placebo-controlled studies have been debated in the revision process of the Declaration of Helsinki. Of particular concern has been the difference between trials comparing inert placebos with experimental treatments, versus comparing the best available treatment with an experimental treatment; and differences between trials in the sponsor's developed countries versus the trial's targeted developing countries.
Some suggest that existing medical treatments should be used instead of placebos, to avoid having some patients not receive medicine during the trial.