Placebo medication use in patient care: a survey of medical interns

The use of placebo medication, long recognized by clinicians, often has serious practical implications, such as patient deception. Past evidence has suggested that resident physicians tend to misuse placebo medication. Interns from two consecutive years of a residency program were surveyed anonymously to assess their knowledge and use of placebos. Of the 74 interns surveyed, 44 (59%) were familiar with placebo use in patient care. Fifty percent of these interns familiar with placebo use had learned about placebos from another physician. All interns who had learned about placebos during their internships had learned from another physician, whereas interns who had gained their knowledge of placebos as medical students were as likely to have learned from the medical literature as they were to have learned from a physician (P = 0.027). Interns aware of placebo use were more likely to consider placebo administration for suspected, factitious pain (P = 0.022). The present study uncovered no relationship between interns' estimations of placebo efficacy and the utility they attributed to placebos in assessing a complaint of pain. This suggests that conceptual inconsistencies underlie their use of placebos. Interns often learn of placebos as medical students and are influenced by physician-mentors. Placebo use in patient care is an area of attention for medical educators.     

Are open‐Label Placebos Ethical? Informed Consent and Ethical Equivocations

The doctor‐patient relationship is built on an implicit covenant of trust, yet it was not until the post‐World War Two era that respect for patient autonomy emerged as an article of mainstream medical ethics. Unlike their medical forebears, physicians today are expected to furnish patients with adequate information about diagnoses, prognoses and treatments. Against these dicta there has been ongoing debate over whether placebos pose a threat to patient autonomy. A key premise underlying medical ethics discussion is the notion that the placebo effect necessitates patient deception. Indeed, the American Medical Association guidelines imply that placebo treatment necessary entails a form of deception. As a consequence of this assumption, the fulcrum of debate on the use of placebo treatment has hinged on whether that deception is ever justified. Recently performed experiments with open‐label transparently prescribed placebos have begun to challenge the notion that deception is necessary in eliciting the placebo effect and such effects necessarily involve a binary distinction between autonomy and beneficence. In this article we focus on the content of disclosures in distinctive open‐label, transparently disclosed placebo studies and inquire whether they might be said to invoke deception in clinical contexts, and if so, whether the deception is unethical. We find that open placebos may be said to involve equivocation over how placebos work. However, drawing on surveys of patient attitudes we suggest that this equivocation appears to be acceptable to patients. We conclude that open placebos fulfil current American Medical Association guidelines for placebo use, and propose future research directions for harnessing the placebo effect ethically.     

Placebo in the treatment of pain

Placebo is the use of the substance or procedure without specific activity for the condition that is trying to be healed. In medicine, benefits of placebo effect are used since 1985 and 1978 placebo effect was first scientifically confirmed. It was found that placebo induced analgesia depends on the release of endogenous opiates in the brain and that the placebo effect can be undone using the opiates antagonist naloxone. Functional magnetic resonance imaging of the brain showed that placebo analgesia was obtained regarding the activation and increased functional relationship between ant. cingulate, prefrontal, orbitofrontal, and insular cortex, nucleus accumlens, amygdala, periaqueduktalne gray matter and spinal cord. Placebo also facilitates descending inhibition of nociceptive reflexes through periacvaeductal gray substance. Placebo effect can be achieved in several ways: by using pharmacological preparations or simulation of operating or other procedures. This phenomenon is associated with perception and expectation of the patient. To achieve the effect of placebo it is essential degree of the suggestions of the person who prescribe a placebo, and the degree of belief of the person receiving the placebo. Expected effect of placebo is to achieve the same effect as the right remedy. Achieved placebo effect depends on the way of presentation. If a substance is presented as harmful, it may cause harmful effects, called 'nocebo" effect. Placebo effect is not equal in all patients, same as the real effect of the drug is not always equal in all patients. Application of placebo in terms of analgesia will cause a positive response in 35% of patients. Almost the same percentage (36%) of patients will respond to treatment with morphine in medium doses (6-8 mg). Therefore, one should remember that response to placebo does not mean that a person simulates the pain and then it is unethical to withhold the correct treatment especially in light of findings that the prefrontal cortex is activated expecting liberation of pain and how this action reduce activities in brain regions responsible for sensation of pain (thalamus, somatosensory cortex and other parts of the cortex). However, the use of placebos is ethically, legally and morally very dubious. The basis for the placebo effect is deception. It undermines honest relationship and trust between doctor and patient which is extremely important for successful treatment. Consciously giving placebos to patients for a condition that can be adequately treated, with prejudice the right of patients to the best care possible, opens up many bioethical issues. Despite all the current knowledge level, placebo effect remains still a scientific mystery.     

Different Placebos,Different Mechanisms,Different Outcomes: Lessons for Clinical Trials

Clinical trials use placebos with the assumption that they are inert, thus all placebos are considered to be equal. Here we show that this assumption is wrong and that different placebo procedures are associated to different therapeutic rituals which, in turn, trigger different mechanisms and produce different therapeutic outcomes. We studied high altitude, or hypobaric hypoxia, headache, in which two different placebos were administered. The first was placebo oxygen inhaled through a mask, whereas the second was placebo aspirin swallowed with a pill. Both placebos were given after a conditioning procedure, whereby either real oxygen or real aspirin was administered for three consecutive sessions to reduce headache pain. We found that after real oxygen conditioning, placebo oxygen induced pain relief along with a reduction in ventilation, blood alkalosis and salivary prostaglandin (PG)E2, yet without any increase in blood oxygen saturation (SO2). By contrast, after real aspirin conditioning, placebo aspirin induced pain relief through the inhibition of all the products of cyclooxygenase, that is, PGD2, PGE2, PGF2, PGI2, thromboxane (TX)A2, without affecting ventilation and blood alkalosis. Therefore, two different placebos, associated to two different therapeutic rituals, used two different pathways to reduce headache pain. The analgesic effect following placebo oxygen was superior to placebo aspirin. These findings show that different placebos may use different mechanisms to reduce high altitude headache, depending on the therapeutic ritual and the route of administration. In clinical trials, placebos and outcome measures should be selected very carefully in order not to incur in wrong interpretations.     

The placebo response: an attachment strategy that counteracts the effects of stress-related dysfunction

The placebo response represents an enigmatic element of therapeutics. The potency of placebo effects is highlighted by the fact that the current gold standard for determining therapeutic efficacy, the randomized controlled clinical trial, is based on identifying treatment responses that are statistically superior to those elicited by a placebo. Although much has been written concerning the phenomenology of placebos, little is known concerning how they are elicited, although recent research has demonstrated that placebo effects are mediated via objective physiological pathways. I have previously argued that the placebo response is a developmental achievement, rooted in implicit procedural memories that are linked to background affects of well-being evoked by a relational dynamic with a caregiver. This article develops this idea further, suggesting that placebo response represents a nervous-system response aimed at countering the dysphoric effects attributable to chronic stress, and that it is dependent on developmental attachment dynamics. A range of behaviors by caregivers that mimic those achieved during secure attachment are suggested to promote placebo responses.     

Mechanisms of placebo effect and of conditioning: neurobiological data in human and animals

A placebo is a sham treatment such as pill, liquid, injection, devoid of biological activity and used in pharmacology as a control for the activity of a drug. In many cases, this placebo induces biological or psychological effects in the human. Two theories have been proposed to explain the placebo effect: the conditioning theory which states that the placebo effect is a conditioned response, and the mentalistic theory for which the patient expectation is the primary basis of the placebo effect. The mechanisms involved in these processes are beginning to be understood through new techniques of investigation in neuroscience. Dopamine and endorphins have been clearly involved as mediators of the placebo effect. Brain imaging has demonstrated that the placebo effect activates the brain similarly as the active drug and in the same brain area. This is the case for a dopamine placebo in the Parkinson'disease, for analgesic-caffeine- or antidepressor-placebo in the healthy subject. It remains to be understood how conditioning and expectancy are able to activate, in the brain, memory loops that reproduce the expected biological response.     

A guide to the pharmacology of placebos.

The placebo effect is capable of relieving pain in a substantial proportion of patients; affective disorders also respond to the administration of inert medication. Changes in objective measures, such as blood pressure and blood glucose levels, demonstrate the action of placebos. The underlying mechanisms are not yet known, but because the nature and strength of the placebo response are governed by the patient''s perceptions, both positive and negative results may be obtained. The complexity of human perception has made it extremely difficult to characterize the people who react. In clinical situations the placebo may be underused as a therapeutic agent, while in clinical trials the effect may be inadequately evaluated; the power and nature of the placebo effect truly warrant greater recognition.     

Possible contribution of quantum-like correlations to the placebo effect: consequences on blind trials

Background

Factors that participate in the biological changes associated with a placebo are not completely understood. Natural evolution, mean regression, concomitant procedures and other non specific effects are well-known factors that contribute to the “placebo effect”. In this article, we suggest that quantum-like correlations predicted by a probabilistic modeling could also play a role.

Results

An elementary experiment in biology or medicine comparing the biological changes associated with two placebos is modeled. The originality of this modeling is that experimenters, biological system and their interactions are described together from the standpoint of a participant who is uninvolved in the measurement process. Moreover, the small random probability fluctuations of a “real” experiment are also taken into account. If both placebos are inert (with only different labels), common sense suggests that the biological changes associated with the two placebos should be comparable. However, the consequence of this modeling is the possibility for two placebos to be associated with different outcomes due to the emergence of quantum-like correlations.

Conclusion

The association of two placebos with different outcomes is counterintuitive and this modeling could give a framework for some unexplained observations where mere placebos are compared (in some alternative medicines for example). This hypothesis can be tested in blind trials by comparing local vs. remote assessment of correlations.

     

Placebo-Induced Somatic Sensations: A Multi-Modal Study of Three Different Placebo Interventions

Somatic sensations induced by placebos are a frequent phenomenon whose etiology and clinical relevance remains unknown. In this study, we have evaluated the quantitative, qualitative, spatial, and temporal characteristics of placebo-induced somatic sensations in response to three different placebo interventions: (1) placebo irritant solution, (2) placebo laser stimulation, and (3) imagined laser stimulation. The quality and intensity of evoked sensations were assessed using the McGill pain questionnaire and visual analogue scales (VAS), while subjects’ sensation drawings processed by a geographic information system (GIS) were used to measure their spatial characteristics. We found that all three interventions are capable of producing robust sensations most frequently described as “tingling” and “warm” that can reach consider-able spatial extent (≤ 205mm^²) and intensity (≤ 80/100 VAS). Sensations from placebo stimulation were often referred to areas remote from the stimulation site and exhibit considerable similarity with referred pain. Interestingly, there was considerable similarity of qualitative features as well as spatial patterns across subjects and placebos. However, placebo laser stimulation elicited significantly stronger and more widespread sensations than placebo irritant solution. Finally, novelty seeking, a character trait assessed by the Temperament and Character Inventory and associated with basal dopaminergic activity, was less pronounced in subjects susceptible to report placebo-induced sensations. Our study has shown that placebo-induced sensations are frequent and can reach considerable intensity and extent. As multiple somatosensory subsystems are involved despite the lack of peripheral stimulus, we propose a central etiology for this phenomenon.     

When and Why Placebo-Prescribing Is Acceptable and Unacceptable: A Focus Group Study of Patients' Views

Background

Surveys of doctors suggest that they use placebos and placebo effects clinically to help patients. However, patients'' views are not well-understood. We aimed to identify when and why placebo-prescribing in primary care might be acceptable and unacceptable to patients.

Methods

A purposive diverse sample of 58 English-speaking adults (18 men; aged 19–80 years) participated in 11 focus groups. Vignettes describing doctors prescribing placebos in primary care were used to initiate discussions. Data were analyzed inductively.

Results

Participants discussed diverse harms and benefits of placebo-prescribing for individual patients, carers, healthcare providers, and society. Two perspectives on placebo-prescribing were identified. First, the “consequentialist” perspective focused on the potential for beneficial outcomes of placebo-prescribing. Here, some participants thought placebos are beneficial and should be used clinically; they often invoked the power of the mind or mind-body interactions. Others saw placebos as ineffective and therefore a waste of time and money. Second, the “respecting autonomy” perspective emphasized the harms caused by the deceptive processes thought necessary for placebo-prescribing. Here, participants judged placebo-prescribing unacceptable because placebo-prescribers deceive patients, thus a doctor who prescribes placebos cannot be trusted and patients'' autonomy is compromised. They also saw placebo-responders as gullible, which deterred them from trying placebos themselves. Overall, the word “placebo” was often thought to imply “ineffective”; some participants suggested alternative carefully chosen language that could enable doctors to prescribe placebos without directly lying to patients.

Conclusions

Negative views of placebos derive from beliefs that placebos do not work and/or that they require deception by the doctor. Positive views are pragmatic in that if placebos work then any associated processes (e.g. mechanisms, deception) are deemed unimportant. Public education about placebos and their effects is warranted and research to identify optimal ways of harnessing placebo effects in clinical practice is needed.     

Placebo Use in the United Kingdom: Results from a National Survey of Primary Care Practitioners

Objectives

Surveys in various countries suggest 17% to 80% of doctors prescribe ‘placebos’ in routine practice, but prevalence of placebo use in UK primary care is unknown.

Methods

We administered a web-based questionnaire to a representative sample of UK general practitioners. Following surveys conducted in other countries we divided placebos into ‘pure’ and ‘impure’. ‘Impure’ placebos are interventions with clear efficacy for certain conditions but are prescribed for ailments where their efficacy is unknown, such as antibiotics for suspected viral infections. ‘Pure’ placebos are interventions such as sugar pills or saline injections without direct pharmacologically active ingredients for the condition being treated. We initiated the survey in April 2012. Two reminders were sent and electronic data collection closed after 4 weeks.

Results

We surveyed 1715 general practitioners and 783 (46%) completed our questionnaire. Our respondents were similar to those of all registered UK doctors suggesting our results are generalizable. 12% (95% CI 10 to 15) of respondents used pure placebos while 97% (95% CI 96 to 98) used impure placebos at least once in their career. 1% of respondents used pure placebos, and 77% (95% CI 74 to 79) used impure placebos at least once per week. Most (66% for pure, 84% for impure) respondents stated placebos were ethical in some circumstances.

Conclusion and implications

Placebo use is common in primary care but questions remain about their benefits, harms, costs, and whether they can be delivered ethically. Further research is required to investigate ethically acceptable and cost-effective placebo interventions.     

Pain and the placebo: what we have learned

Despite the recent blossoming of rigorous research into placebo mechanisms and the long-standing use of placebos in clinical trials, there remains widespread and profound misunderstanding of the placebo response among both practicing physicians and clinical researchers. This review identifies and clarifies areas of current confusion about the placebo response (including whether it exists at all), describes its phenomenology, and outlines recent advances in our knowledge of its underlying psychological and neural mechanisms. The focus of the review is the placebo analgesic response rather than placebo responses in general, because much of the best established clinical and experimental work to date has been done on this type of placebo response. In addition, this subfield of placebo research offers a specific neural circuit hypothesis capable of being integrated with equally rigorous experimental work on the psychological (including social psychological) and clinical levels. In this sense, placebo analgesia research bears all the marks of a genuine multilevel interdisciplinary research paradigm in the making, one that could serve as a model for research into other kinds of placebo responses, as well as into other kinds of mind-body responses.     

Research ethics and the use of placebo: status of the debate in Canada

The question of the use of the placebo is one of the most controversial in the field of the ethics of research today. The use of the placebo remains the standard practice of biomedical research in spite of the fact that various revisions of the Helsinki Declaration have sought to limit its use. In Canada, the Tri-council policy statement: Ethical conduct for research involving humans adopted a very restrictive position with respect to the use of placebos, precisely defining the situations in which its use would meet the demands of ethical research. The positions taken by the various ethical decision-making bodies are, however, hardly shared by regulatory bodies such as the Food and drug administration (FDA), the Council for international organization of medical sciences (CIOMS) or the European agency for the evaluation of medicinal products (EMEA). This divergence of opinions reveals two quite different conceptions of what constitutes the ethical. In the case of decision-making bodies in the ethical field, it is clearly medicine's Hippocratic Oath which explains their reluctance to use placebos. The first responsibility of the doctor is to "do no harm" to his or her patient. This duty is inherent to the medical profession and as such is not grounded in the view of medicine as a contract for care. In the case of regulatory bodies, it is the vision of "medicine as contract" which is in view; and it is this notion that justifies the use of placebos once free and informed consent has been obtained. It is also worth noting that these regulatory bodies make frequent use of arguments based on utilitarian ends. In an unprecedented move, the World medical association published in October 2001 a clarification note about the use of placebos. An analysis of this text raises the question about its real meaning: clarification or concession?     

An enactive account of placebo effects

Placebos are commonly defined as ineffective treatments. They are treatments that lack a known mechanism linking their properties to the properties of the condition on which treatment aims to intervene. Given this, the fact that placebos can have substantial therapeutic effects looks puzzling. The puzzle, we argue, arises from the relationship placebos present between culturally meaningful entities (such as treatments or therapies), our intentional relationship to the environment (such as implicit or explicit beliefs about a treatment’s healing powers) and bodily effects (placebo responses). How can a mere attitude toward a treatment result in appropriate bodily changes? We argue that an ‘enactive’ conception of cognition accommodates and renders intelligible the phenomenon of placebo effects. Enactivism depicts an organism’s adaptive bodily processes, its intentional directedness, and the meaningful properties of its environment as co-emergent aspects of a single dynamic system. In doing so it provides an account of the interrelations between mind, body and world that demystifies placebo effects.     

Placebo analgesia: cognitive influences on therapeutic outcome

The therapeutic response to a drug treatment is a mixture of direct pharmacological action and placebo effect. Therefore, harnessing the positive aspects of the placebo effect and reducing the negative ones could potentially benefit the patient. This article is aimed at providing an overview for clinicians of the importance of contextual psychosocial variables in determining treatment response, and the specific focus is on determinants of the placebo response. A better understanding of the physiological, psychological, and social mechanisms of placebo may aid in predicting which contexts have the greatest potential for inducing positive treatment responses. We examine the evidence for the role of psychological traits, including optimism, pessimism, and the effect of patient expectations on therapeutic outcome. We discuss the importance of the patient-practitioner relationship and how this can be used to enhance the placebo effect, and we consider the ethical challenges of using placebos in clinical practice.     

Placebo analgesia: cognitive influences on therapeutic outcome

The therapeutic response to a drug treatment is a mixture of direct pharmacological action and placebo effect. Therefore, harnessing the positive aspects of the placebo effect and reducing the negative ones could potentially benefit the patient. This article is aimed at providing an overview for clinicians of the importance of contextual psychosocial variables in determining treatment response, and the specific focus is on determinants of the placebo response. A better understanding of the physiological, psychological, and social mechanisms of placebo may aid in predicting which contexts have the greatest potential for inducing positive treatment responses. We examine the evidence for the role of psychological traits, including optimism, pessimism, and the effect of patient expectations on therapeutic outcome. We discuss the importance of the patient-practitioner relationship and how this can be used to enhance the placebo effect, and we consider the ethical challenges of using placebos in clinical practice.     

The Use of Placebo and Non-Specific Therapies and Their Relation to Basic Professional Attitudes and the Use of Complementary Therapies among German Physicians – A Cross-Sectional Survey

We aimed to investigate the use of placebos (e.g. saline injections) and non-specific treatments (e.g. vitamin supplements in individuals without a relevant deficiency) among physicians working in private practices in Germany, and how such use is associated with the belief in and the use of complementary and alternative treatments, and basic professional attitudes. A four-page questionnaire was sent to nationwide random samples of general practitioners (GP), internists and orthopaedists working in private practices. The response rate was 46% (935 of 2018). 24% of GPs, 44% of internists and 57% of orthopaedists had neither used pure placebos nor non-specific therapies in the previous 12 months. 11% percent of GPs, 12% of internists and 7% of orthopaedists had exclusively used pure placebos; 30%, 33% and 26%, respectively, had exclusively used non-specific therapies; 35%, 12% and 9% had used both. Age, sex and agreement to the statement that physicians should harness placebo effects were not significantly associated with any pattern of use. Exclusive use of pure placebos was associated with being a GP, being an internist, and having unorthodox professional views. In addition to these three factors, a lower use of CAM therapies and a wish for having more time was associated with the exclusive use of non-specific therapies. Among physicians using both pure placebo and non-specific therapies, heterodox views were also somewhat more pronounced. However, associations were particularly strong for being a GP (Odds ratio 11.6 (95%CI 6.41; 21.3)) and having orthodox views (Odds ratio 0.10 (95%CI 0.06; 0.18)) among this group. In conclusion, the use of placebos and non-specific treatments varies strongly between medical specialties and is associated with basic professional attitudes. The findings support the view that the use of placebos and, in particular, of non-specific therapies is primarily a coping behaviour for difficult and uncertain situations.     

Selenium content and distribution in rat tissues irradiated with gamma rays

The effects of supplementation with selenous yeast and ionizing radiation on selenium (Se) content and distribution were evaluated in rat tissues (liver, kidney, spleen, heart, muscle, blood, front brain, hind brain, hypothalamus, pituitary, adrenal glands, testes, and hair). This study had 16 Se-supplemented (0.5 μg Se/d) and 16 placebo adult male Wistar rats. One half of the animals (eight Se-supplemented and eight placebos) were irradiated with a single dose of 4.2 Gy from a Co-60 source and sacrificed 7 d after irradiation along with nonirradiated animals and analyzed for Se content determination. The data obtained showed that selenous yeast supplementation increased Se levels in rat tissues (highest increases in hypothalamus, 161%; hind brain, 126%; spleen, 110%; and adrenal gland, 105%). Ionizing radiation induced significant changes in Se content and distribution (decrease in liver, blood, hair, femoral muscle, spleen, and hypothalamus; increase in kidney, testes, adrenal glands, and brain of placebo group). Supplementation with selenous yeast reduces changes in Se content and distribution after irradiation. It seems that the animal tissue susceptibility to oxidative damage may be correlated to their ability to retain Se in tissues.     

New insights into the placebo and nocebo responses

In modern medicine, the placebo response or placebo effect has often been regarded as a nuisance in basic research and particularly in clinical research. The latest scientific evidence has demonstrated, however, that the placebo effect and the nocebo effect, the negative effects of placebo, stem from highly active processes in the brain that are mediated by psychological mechanisms such as expectation and conditioning. These processes have been described in some detail for many diseases and treatments, and we now know that they can represent both strength and vulnerability in the course of a disease as well as in the response to a therapy. However, recent research and current knowledge raise several issues that we shall address in this review. We will discuss current neurobiological models like expectation-induced activation of the brain reward circuitry, Pavlovian conditioning, and anxiety mechanisms of the nocebo response. We will further explore the nature of the placebo responses in clinical trials and address major questions for future research such as the relationship between expectations and conditioning in placebo effects, the existence of a consistent brain network for all placebo effects, the role of gender in placebo effects, and the impact of getting drug-like effects without drugs.     

The relation of emotions to placebo responses

The hypothesis put forth is that expectations of treatment effects reduce negative emotions and thereby reduce symptoms, e.g. pain. Negative emotions increase pain, and it is hypothesized that placebos reduce pain by reducing negative emotions, i.e. feelings of nervousness, fear and anxiety. Placebo analgesia has been shown to be mediated via opioid activity, and relaxation increases opioid activity. The placebo acquires its relaxing effect due to verbal information that pain will be reduced, or due to associations between the placebo and the reduction in pain after effective treatment. Thus, the placebo signals that unpleasantness will be less after administration of the placebo. This involves negative reinforcement which is due to activation of a dopaminergic system that has been found to be activated during placebo analgesia and is involved in positive emotions. The nocebo effect of increased pain is, consistent with this model, because of increased fear and anxiety. The new aspect of the presented model is the hypothesis that expectations reduce negative emotions, and that negative reinforcement that involves the dopaminergic reinforcement system should be a contributor to placebo responses.