More than fifteen years ago, it was noted that the failure rate of antidepressant clinical trials was high, and such negative outcomes were thought to be related to the increasing magnitude of ...placebo response. However, there is considerable debate regarding this phenomenon and its relationship to outcomes in more recent antidepressant clinical trials. To investigate this, we accessed the US Food and Drug Administration (FDA) reviews for sixteen antidepressants (85 trials, 115 trial arms, 23,109 patients) approved between 1987 and 2013. We calculated the magnitude of placebo and antidepressant responses, antidepressant‐placebo differences, as well as the effect sizes and success rates, and compared these measures over time. Exploratory analysis investigated potential changes in trial design and conduct over time. As expected, the magnitude of placebo response has steadily grown in the past 30 years, increasing since 2000 by 6.4% (r=0.46, p<0.001). Contrary to expectations, a similar increase has occurred in the magnitude of antidepressant response (6.0%, r=0.37, p<0.001). Thus, the effect sizes (0.30 vs. 0.29, p=0.42) and the magnitude of antidepressant‐placebo differences (10.5% vs. 10.3%, p=0.37) have remained statistically equivalent. Furthermore, the frequency of positive trial arms has gone up in the past 15 years (from 47.8% to 63.8%), but this difference in frequency has not reached statistical significance. Trial design features that were previously associated with a possible lower magnitude of placebo response were not implemented, and their relationship to the magnitude of placebo response could not be replicated. Of the 34 recent trials, two implemented enhanced interview techniques, but both of them were unsuccessful. The results of this study suggest that the relationship between the magnitude of placebo response and the outcome of antidepressant clinical trials is weak at best. These data further indicate that antidepressant‐placebo differences are about the same for all of the sixteen antidepressants approved by the FDA in the past thirty years.
Objective
To examine how primary care physicians define placebo concepts, use placebos in clinical practice, and view open‐label placebos (OLPs).
Design
Semi‐structured focus groups that were ...audio‐recorded and content‐coded.
Methods
Two focus groups with a total of 15 primary care physicians occurred at medical centres in the New England region of the United States. Prior experience using placebo treatments and attitudes towards open‐label placebos were explored. Themes were analysed using an inductive data‐driven approach.
Results
Physicians displayed a nuanced understanding of placebos and placebo effects in clinical contexts which sometimes focused on relational factors. Some respondents reported that they prescribed treatments with no known pharmacological effect for certain conditions and symptoms (‘impure placebos’) and that such prescriptions were more common for pain disorders, functional disorders, and medically unexplained symptoms. Opinions about OLP were mixed: Some viewed OLPs favourably or considered them ‘harmless’; however, others strongly rejected OLPs as disrespectful to patients. Other issues in relation to OLPs included the following: lack of guidelines, legal and reputational concerns, and the notion that such treatments would run counter to customary medical practice.
Conclusions
A number of physicians reported prescribing impure placebos in clinical care. Although some primary care physicians were resistant to the possibility of recommending OLPs, others regarded OLPs more favourably, viewing them as potential treatments, albeit with restricted potential.
Statement of contribution
What is already known?
Many physicians report prescribing drugs for the purposes of eliciting a placebo effect.
Initial evidence for the efficacy of open‐label placebos is promising.
What does this study add?
A more nuanced description of the circumstances under which primary care physicians report placebo prescribing.
A qualitative account of physician attitudes about using open‐label placebos in clinical practice.
The placebo effect: To explore or to exploit? Barnes, Kirsten; Rottman, Benjamin Margolin; Colagiuri, Ben
Cognition,
September 2021, 2021-09-00, 20210901, Letnik:
214
Journal Article
Recenzirano
How people choose between options with differing outcomes (explore-exploit) is a central question to understanding human behaviour. However, the standard explore-exploit paradigm relies on gamified ...tasks with low-stake outcomes. Consequently, little is known about decision making for biologically-relevant stimuli. Here, we combined placebo and explore-exploit paradigms to examine detection and selection of the most effective treatment in a pain model. During conditioning, where ‘optimal’ and ‘suboptimal’ sham-treatments were paired with a reduction in electrical pain stimulation, participants learnt which treatment most successfully reduced pain. Modelling participant responses revealed three important findings. First, participants' choices reflected both directed and random exploration. Second, expectancy modulated pain – indicative of recursive placebo effects. Third, individual differences in terms of expectancy during conditioning predicted placebo effects during a subsequent test phase. These findings reveal directed and random exploration when the outcome is biologically-relevant. Moreover, this research shows how placebo and explore-exploit literatures can be unified.
Summary
A lack of sleep can increase appetite, particularly for high‐calorie food. The current study tested the effects of an open‐label placebo for improving sleep quality and reducing food cue ...reactivity. In open‐label placebo interventions, placebo recipients are informed that they are receiving a placebo without a pharmacologically active substance. Participants (n = 150) were randomly allocated to one of three groups that received either an open‐label placebo to improve sleep quality, a deceptive placebo (“melatonin”), or no placebo. The placebo was administered daily before bedtime for 1 week. Sleep quality and reactivity to high‐calorie food cues (appetite, visual attention to food images) were assessed. The deceptive placebo (but not the open‐label placebo) reduced reported sleep‐onset latency. The open‐label placebo decreased perceived sleep efficiency. The placebo interventions did not change food cue reactivity. This study demonstrated that open‐label placebos do not present an alternative to deceptive placebos for improving sleep quality. The undesirable open‐label placebo effects found warrant further exploration.
Background and purpose
On the basis of occasional strong placebo responses, increased susceptibility to placebo has been proposed as a characteristic of functional neurological disorder (FND). The ...aim of this study was to clarify whether people with FND have a stronger placebo analgesic response than healthy controls.
Methods
A study using a classic placebo paradigm, with additional conditioning and open‐label components, was performed in 30 patients with FND, and in 30 healthy controls. Ratings of mildly to moderately painful electrotactile stimuli were compared before and after the application of a placebo “anaesthetic” cream versus a control cream, after an additional conditioning exposure, and after full disclosure (open‐label component).
Results
Pain intensity ratings at the placebo compared to the control site were similarly reduced in both groups. The conditioning exposure had no additional effect. After placebo disclosure a residual analgesic effect remained.
Conclusion
Patients with FND did not have stronger placebo responses than healthy controls. The notion of generally increased suggestibility or increased suggestibility to placebo in FND seems mistaken. Instead, occasional dramatic placebo responses may occur because functional symptoms are inherently more changeable than those due to organic disease.
Although dramatic placebo responses occasionally occur in functional neurological disorder (FND), the susceptibility to placebo per se was not enhanced in a relatively large group of people with FND compared to healthy controls. The common notion of hypersuggestibility to placebo in this condition therefore needs to be challenged. Instead, occasional dramatic placebo effects might occur because functional symptoms are inherently more changeable than organic symptoms.
Placebo trials in research are generally looked upon unfavorably. They are only tolerated when a standard of care treatment control is not available or feasible. In developing countries, where a ...significant portion of drug trials and medical research studies are conducted, placebo driven trials are more commonplace, but not without controversy. The atrocities of Nazi Germany and the Tuskegee Syphilis study in the United States have put humanitarians and bioethicists on high alert to prevent similar injustice. It is not surprising that the arguments against placebo driven studies are often made from the point-of-view of a parent or guardian looking after the well-being of a child participating in research. What about the patient’s perspective? The intention of this paper is to evaluate if placebo trials in developing countries violate any of the four bioethical principles. Autonomy Simply stated, the principle of autonomy encompasses an individual's right to control what happens to their body. In Western culture, this is where informed consent plays its role. A patient should be able to make a decision whether or not they want to participate in a drug trial that includes a placebo arm. However, they need to understand all major aspects of the trial and treatment in order to consent. Can an individual make an informed decision without a complete understanding? Patient A lives in a developing country and is HIV positive. He is starting to show symptoms, and a major pharmaceutical company is starting a drug trial that includes his village. The researchers explain that there is a placebo arm to the study, telling him that he may or may not get the actual medicine. However, he will get medical care throughout the study, which will last a couple of years. Patient A knows that if he does not participate in the trial, he will not get medical treatment for anything. If Patient A makes a decision based on whether or not he gets medical treatment, is that an informed decision? Does he have to show some level of awareness and comprehension about the placebo or experimental drug and possible outcomes? It is possible to make an informed decision about participating in a trial solely on the basis of receiving medical care. Beneficence The researchers should act in the best interest of the patient. Well-intentioned individuals argue that placebo arm studies should not be conducted because it is not acting in the best interest of the patients assigned to the placebo group. In many instances, this is true, especially in the United States, where a patient in a placebo group would have access to another form of treatment if they dropped out of the study. Therefore, being randomized to the placebo group puts the participant in a condition that is worse than if they were not enrolled in the study. A research participant in a developing country is faced with different circumstances because of different levels of access to medical treatment. Those in the placebo group are not worse off than if they declined to participate in the study; they are better off because they are going to be provided medical care during the duration of the study. Assuming there is clinical equipoise in the research study to begin with, it is not known whether the placebo group is going to be better off or worse off that the treatment group. It is therefore in the best interest of the patients to allow the study with the placebo arm to take place because both arms of the study provide medical care. Nonmaleficence The researchers should not harm the patients involved in the research study. The main question with nonmaleficence is: is the placebo group being harmed? Some might argue that, when available, the omission of treatment, or standard of care, can be construed as harm being done to an individual in the placebo group. A good example to illustrate this is a hypothetical research study for a new malarial drug. Ideally, the new drug would be compared to the current standard of care for malaria. Comparing the new malaria drug to a placebo is clearly is not as good as comparing it to standard of care in terms of benefit to the subjects enrolled in the study. However, the difference of “good” is relative. It is difficult to keep in mind, that prior to the study, it is likely that the patients were getting no medical care. Therefore, the difference between providing a placebo, including medical care, and nothing is much greater than between a placebo and the standard of treatment. Is not providing the patient with standard of care harming them? It would be better for them to get the standard of care, but it is also acceptable that they are being provided with medical treatment and a placebo.1 It is similar to providing compensation for participating in a trial in the developing world. If a patient in a developing country was compensated the same amount as a patient in the United States, it would be deemed unethical and coercive because it would be an incredibly large sum of money. I am not implying that providing treatment and monetary compensation are equivalent, but it is worth considering. Another way to look at whether or not patients in the placebo arm are being harmed is by doing a risk/benefit analysis. What are the risks? The patient who gets randomized to the placebo arm of the study is not bearing any additional risk by being randomized to the placebo group. If they did not sign up for the study, they would not be receiving any treatment. The placebo group is also not getting any treatment. What about benefits? The patient does benefit from access to medical care for participating in the study. If they are suffering from secondary infection or another illness, they will still be treated. In fact, the placebo group is subjected to less risk than the experimental group. The experimental group gets the same medical care, but is given an experimental drug. Participants in this group have increased risk, with side-effects, but also have greater potential benefits. This is different from a placebo group in a country like the United States, where placing them in a placebo group would be doing them harm. A placebo group in the US would be subjected to additional risk because they have access to medical care and the trial would prevent them from being able to pursue the current standard of care. Justice Is there a fair distribution of the risks and benefits on the participants in the study? Are the patients risking too much by being randomized into a placebo group or the experimental group? Let us assume that a research study with an experimental arm and a control (standard of care) arm does satisfy the fair distribution of risks and benefits requirement. If that assumption is made, then the experimental and placebo study should also satisfy the requirement. Unless the drug being tested is going to only help developing countries, like a new malaria drug, the gains from studies involving patients in developing countries are going to be realized by the developed world.2 Having a standard of care instead of a placebo is not going to change the “fair” distribution of risks borne by the participants during the trial or the benefits the world receives from the results of the study. Therefore, the risks and benefit analysis has to be done on the participants in the study. Once again, the placebo group is getting medical care that they would not be receiving otherwise. They are not bearing any additional risk by participating in the trial. The benefits gained from the study by the participants are going to be less for the placebo study versus the standard of care study, but not enough to disrupt a fair distribution of risks and benefits. Making the case that placebo studies in developing countries are ethical is not a typical approach. It takes a deeper understanding of the frame of mind of the candidate and the environment they live in. Often ethicists use the structure and values of the United States to evaluate an issue, but they are sometimes insufficient. Pharmaceutical companies should use control groups that are given standard of care instead of placebos. Whether or not they should be required to do so is another question. From the perspective of the participants in research studies in the developing world, having a standard of care or placebo is not going to be a determining factor in their decision to participate. NOTES 1 After the study is concluded, without continuing to provide anti-malarial drugs to the community indefinitely, the individuals in the study will continue to get malaria. 2 Would testing a new malaria drug that uses a standard of care as the control be ethical? In that situation, the control participants are getting a treatment that works and medical care. The experimental group is getting an experimental drug that may or may not work and medical care. Is that ethical?
Objective: Research on placebo/nocebo effects suggests that expectations can influence treatment outcomes, but placebo/nocebo effects are not always evident. This research demonstrates that a ...provider's social behavior moderates the effect of expectations on physiological outcomes. Methods: After inducing an allergic reaction in participants through a histamine skin prick test, a health care provider administered a cream with no active ingredients and set either positive expectations (cream will reduce reaction) or negative expectations (cream will increase reaction). The provider demonstrated either high or low warmth, or either high or low competence. Results: The impact of expectations on allergic response was enhanced when the provider acted both warmer and more competent and negated when the provider acted colder and less competent. Conclusion: This study suggests that placebo effects should be construed not as a nuisance variable with mysterious impact but instead as a psychological phenomenon that can be understood and harnessed to improve treatment outcomes.
•Even without deception, placebo leads to less perceived sadness.•Open-label placebo affects perceived sadness but not on physiological measures.•Findings contribute to a better understanding of ...open-label placebo effects on mood.
Recent studies demonstrate substantial effects of deceptive placebo on experimentally induced sadness, even on autonomic activity. Whether deception is necessary, remains to be elucidated. We investigated the effect of an open-label placebo (OLP) treatment, i.e. an openly administered placebo delivered with a convincing rationale for its sadness-protecting effect.
Eighty-four healthy females were randomized to an OLP group or a no-treatment control group. All participants received the same detailed information about the OLP effect, only the OLP group received an OLP nasal spray. Before and after the OLP intervention, participants underwent a sad mood induction procedure combining self-deprecating statements (Velten's method) and sad music. Sadness was assessed by the Positive and Negative Affect Schedule (PANAS-X). Autonomic activity was measured continuously.
Participants in the OLP group reported a significantly attenuated increase in sadness upon mood induction and less sadness after induction compared to the control group (d = 0.79). Regardless of intervention, heart rate decreased during mood inductions with a more pronounced deceleration in the second mood induction.
Generalizability is limited due to the selective sample and the reliance on an experimentally controlled mood induction.
OLP treatment had a beneficial effect on perceived sadness, at least at the subjective level. Hence, deception may not necessarily be required for placebos to modulate experienced sad mood. Investigating the beneficial effects of OLP in (sub-)clinical samples would seem a promising and required next step towards a clinical use of placebo-associated positive treatment expectations.
There is growing evidence that open-label placebo (OLP) may be an efficacious treatment of chronic and functional conditions. However, patient-level predictors of response to OLP have not been ...clearly identified. The aim of this study is to evaluate the psychological predictors of response to OLP and to compare this to double-blind placebo (DBP) and no-pill control (NPC).
This study is a secondary analysis of data collected in a 6-week randomized controlled trial evaluating placebo effects in irritable bowel syndrome (IBS). The primary outcome was change in IBS severity. Hierarchical linear regression identified predictors of placebo response in general and compared them between those randomized to OLP, DBP, and NPC. Predictor variables included personality traits, generalized anxiety, depression, visceral sensitivity (a measure of symptom-specific anxiety), and pain catastrophizing.
A total of 210 participants (mean age = 42.3 years, 73.3% female) were included. Regression models revealed that visceral sensitivity was a predictor of response to OLP and NPC but not DBP. Interestingly, the effects were opposite, with high visceral sensitivity predicting less improvement in NPC and more improvement in OLP. Pain catastrophizing was a negative predictor of response to OLP (i.e., high pain catastrophizing was associated with less improvement in OLP). Neither visceral sensitivity nor pain catastrophizing played a significant role for response to DBP.
IBS participants who score low on the Pain Catastrophizing Scale but high on the Visceral Sensitivity Index seem to benefit particularly from OLP. Our study suggests that different psychological mechanisms may be involved in DBP and OLP interventions.
It is important to know the extent of the placebo effect in designing randomized controlled trials for patients with nonalcoholic steatohepatitis (NASH), to accurately calculate sample size and ...define treatment endpoints.
We performed a systematic review and meta-analysis of the placebo groups from randomized controlled trials of adults with NASH that provided histologic and/or magnetic resonance image-based assessments. We identified trials through a comprehensive search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus, from each database's inception through January 2, 2018.
We identified 39 randomized controlled trials, comprising 1463 patients who received placebo. Histologic assessment data (the nonalcoholic fatty liver disease activity scores, NAS) were available from 956 patients; magnetic resonance spectroscopy data were available from 295 patients and magnetic resonance proton density fat fraction measurements from 61 patients. Overall, 25% of patients given placebo had an improvement in NAS by 2 or more points (95% CI, 21%-29%) with a small amount of heterogeneity (I
= 27%). There were improvements by at least 1 point in steatosis scores of 33% ± 3% of patients, in hepatocyte ballooning scores of 30% ± 3% of patients, in lobular inflammation scores of 32% ± 3% of patients, and in fibrosis scores of 21% ± 3% of patients, with a moderate amount of heterogeneity among trials (I
range, 51%-63%). Patients given placebo had a statistically significant improvement in NAS (by 0.72 ± 0.19), with a large amount of heterogeneity (I
= 96%). Univariate and multivariate meta-regression showed that trials with a higher baseline NAS, those conducted in South America, and those in which patients had a decrease in body mass index, were associated with greater improvements in NAS among patients given placebo. Patients given placebo had significant reductions in intrahepatic triglyceride, measured by magnetic resonance spectroscopy (by 1.45% ± 0.54%) with moderate heterogeneity (I
= 40%), and in magnetic resonance proton density fat fraction (by 2.43 ± 0.89), without heterogeneity (I
= 0). Mean serum levels of alanine and aspartate aminotransferases decreased significantly (by 11.7 ± 3.8 U/L and 5.9 ± 2.1 U/L, respectively; P < .01 for both).
In a meta-analysis of randomized controlled trials of NASH, patients given placebo have significant histologic, radiologic, and biochemical responses. The placebo response should be considered in designing trials of agents for treatment of NASH.
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