Placebo Devices as Effective Control Methods in Acupuncture Clinical Trials: A Systematic Review

While the use of acupuncture has been recognised by the World Health Organisation, its efficacy for many of the common clinical conditions is still undergoing validation through randomised controlled trials (RCTs). A credible placebo control for such RCTs to enable meaningful evaluation of its efficacy is to be established. While several non-penetrating acupuncture placebo devices, namely the Streitberger, the Park and the Takakura Devices, have been developed and used in RCTs, their suitability as inert placebo controls needs to be rigorously determined. This article systematically reviews these devices as placebo interventions. Electronic searches were conducted on four English and two Chinese databases from their inceptions to July 2014; hand searches of relevant references were also conducted. RCTs, in English or Chinese language, comparing acupuncture with one of the aforementioned devices as the control intervention on human participants with any clinical condition and evaluating clinically related outcomes were included. Thirty-six studies were included for qualitative analysis while 14 were in the meta-analysis. The meta-analysis does not support the notion of either the Streitberger or the Park Device being inert control interventions while none of the studies involving the Takakura Device was included in the meta-analysis. Sixteen studies reported the occurrence of adverse events, with no significant difference between verum and placebo acupuncture. Author-reported blinding credibility showed that participant blinding was successful in most cases; however, when blinding index was calculated, only one study, which utilised the Park Device, seemed to have an ideal blinding scenario. Although the blinding index could not be calculated for the Takakura Device, it was the only device reported to enable practitioner blinding. There are limitations with each of the placebo devices and more rigorous studies are needed to further evaluate their effects and blinding credibility.     

On confidence bounds for the ratio of net differences in the "gold standard" design with reference, experimental, and placebo treatment

The three-arm clinical study including a placebo has been recommended to be the preferred study design for the comparison of an experimental treatment relative to a reference treatment. In a confirmatory three-arm study multiplicity issues arise that are not present in two-arm studies. In the past a successful demonstration of superiority of the reference over placebo has been regarded a prerequisite validation step for the demonstration of superiority of the experimental treatment over placebo. However, for an investigator this last comparison is the most critical one. In a clinical study the demonstration of superiority of the experimental treatment over placebo is a result of its own value and this should therefore not be made dependent on tests that are of higher priority in a hierarchical test procedure. This can be achieved through a symmetrical formulation of Fieller's method for constructing confidence intervals for ratio of the expected values from normally distributed variables. In the symmetrical formulation the different meanings of nominator and denominator disappear, and simultaneous statements for comparisons between the experimental treatment and placebo, reference treatment and placebo, and reference and experimental treatment can be made. This is accomplished by moving the discussion on confidence sets from the line of real numbers to the unit circle which allows representing confidence sectors always as connected sets, gives always simple geometrical interpretations, and is easy to be transformed back to the real numbers if the traditional calculations behave well. The proposed procedures provides additional insight in existing methods but does obviously not answer the clinical question whether or not the demonstration of superiority of the reference treatment over placebo is a necessary validation step for further comparisons.     

The placebo response in clinical trials: more questions than answers

Meta-analyses and re-analyses of trial data have not been able to answer some of the essential questions that would allow prediction of placebo responses in clinical trials. We will confront these questions with current empirical evidence. The most important question asks whether the placebo response rates in the drug arm and in the placebo arm are equal. This 'additive model' is a general assumption in almost all placebo-controlled drug trials but has rarely been tested. Secondly, we would like to address whether the placebo response is a function of the likelihood of receiving drug/placebo. Evidence suggests that the number of study arms in a trial may determine the size of the placebo and the drug response. Thirdly, we ask what the size of the placebo response is in 'comparator' studies with a direct comparison of a (novel) drug against another drug. Meta-analytic and experimental evidence suggests that comparator studies may produce higher placebo response rates when compared with placebo-controlled trials. Finally, we address the placebo response rate outside the laboratory and outside of trials in clinical routine. This question poses a serious challenge whether the drug response in trials can be taken as evidence of drug effects in clinical routine.     

A direct advance on advance directives

Advance directives (ADs), which are also sometimes referred to as 'living wills', are statements made by a person that indicate what treatment she should not be given in the event that she is not competent to consent or refuse at the future moment in question. As such, ADs provide a way for patients to make decisions in advance about what treatments they do not want to receive, without doctors having to find proxy decision-makers or having recourse to the doctrine of necessity. While patients can request particular treatments in an AD, only refusals are binding. This paper will examine whether ADs safeguard the autonomy and best interests of the incompetent patient, and whether legislating for the use of ADs is justified, using the specific context of the legal situation in the United Kingdom to illustrate the debate. The issue of whether the law should permit ADs is itself dependent on the issue of whether ADs are ethically justified; thus we must answer a normative question in order to answer the legislative one. It emerges that ADs suffer from two major problems, one related to autonomy and one to consent. First, ADs' emphasis on precedent autonomy effectively sentences some people who want to live to death. Second, many ADs might not meet the standard criteria for informed refusal of treatment, because they fail on the crucial criterion of sufficient information. Ultimately, it transpires that ADs are typically only appropriate for patients who temporarily lose physical or mental capacity.     

How to Study Placebo Responses in Motion Sickness with a Rotation Chair Paradigm in Healthy Participants

Placebo responses occur in every medical intervention when patients or participants expect to receive an effective treatment to relieve symptoms. However, underlying mechanisms of placebo responses are not fully understood. It has repeatedly been shown that placebo responses are associated with changes in neural activity but for many conditions it is unclear whether they also affect the target organ, such as the stomach in motion sickness. Therefore, we present a methodology for the multivariate assessment of placebo responses by subjective, behavioral and objective measures in motion sickness with a rotation chair paradigm. The physiological correlate of motion sickness is a shift in gastric myoelectrical activity towards tachygastria that can be recorded with electrogastrography. The presented study applied the so-called balanced placebo design (BPD) to investigate the effects of ginger compared to placebo and the effects of expectations by verbal information. However, the study revealed no significant main or interactional effects of ginger (as a drug) or information on outcome measures but showed interactions when sex of participants and experimenters are taken into considerations. We discuss limitations of the presented study and report modifications that were used in subsequent studies demonstrating placebo responses when rotation speed was lowered. In general, future placebo studies have to identify the appropriate target organ for the studied placebo responses and to apply the specific methods to assess the physiological correlates.     

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.     

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.     

Factors Affecting Blood Pressure Variability: Lessons Learned from Two Systematic Reviews of Randomized Controlled Trials

Systematic reviews can often reveal much more than the original objective of the work. The objectives of this retrospective analysis were to answer three basic questions about blood pressure variability: 1) Does blood pressure entry criterion have an effect on baseline blood pressure variability? 2) Do thiazide diuretics have a significant effect on blood pressure variability? and 3) Does systolic blood pressure vary to the same degree as diastolic blood pressure? This analysis of blood pressure variability is based on resting standardized research setting BP readings from two systematic reviews evaluating blood pressure lowering efficacy of thiazide diuretics from double blind randomized controlled trials in 33,611 patients with primary hypertension. The standard deviation reported in trials was the focus of the research and the unit of analysis. When a threshold systolic or diastolic blood pressure value is used to determine entry into a trial, baseline variability is significantly decreased, systolic from 14.0 to 9.3 mmHg and diastolic from 8.4 to 5.3 mmHg. Thiazides do not change BP variability as the standard deviation and coefficient of variation of systolic blood pressure and diastolic blood pressure did not differ between thiazide and placebo groups at end of treatment. The coefficient of variation of systolic blood pressure was significantly greater than the coefficient of variation of diastolic blood pressure. Entry criterion decreases the baseline blood pressure variability. Treatment with a thiazide diuretic does not affect blood pressure variability. Systolic blood pressure varies to a greater degree than diastolic blood pressure.     

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?     

Risk-related standards of competence: continuing the debate over risk-related standards of competence

This discussion paper addresses Ian Wilks' defence of the risk-related standard of competence that appears in Bioethics 11 . Wilks there argues that the puzzle posed by Mark Wicclair in Bioethics 5 against Dan Brock's argument in favour of a risk-related standard of competence — namely that Brock's argument allows for situations of asymmetrical competence — is not a genuine problem for a risk-related standard of competence. To show this, Wilks presents what he believes to be two examples of real situations in which asymmetrical competence arises.
I argue that insofar as Wilks equivocates two senses of competence in his examples — namely, competence to perform a task and competence in performing a task — Wilks is unable to illustrate the existence of real situations of asymmetrical competence. By examining the way in which Wilks equivocates two senses of competence in his examples, and by applying the results of this examination to the problem of patient competency within the medical field, I argue that not only does Wilks fail to show that situations of asymmetrical competence exist, but he is also unable to provide a foundation for understating how the risk-related standard of competence can strike a balance between an individual's autonomy and benevolent intervention.
I thus conclude that insofar as Wilks fails to answer the objections raised by Wicclair and others against the risk-related standard of competence, the risk-related standard of competence continues to be undermined by the problem of asymmetrical competence.     

REEXAMINATION OF THE ETHICS OF PLACEBO USE IN CLINICAL PRACTICE

A placebo is a substance or intervention believed to be inactive, but is administered by the healthcare professional as if it was an active medication. Unlike standard treatments, clinical use of placebo usually involves deception and is therefore ethically problematic. Our attitudes toward the clinical use of placebo, which inevitably includes deception or withholding information, have a tremendous effect on our practice regarding truth‐telling and informed consent. A casual attitude towards it weakens the current practice based on shared decision‐making and mutual trust between patients and healthcare professionals. Issues concerning the clinical use of placebo are thus intimately related to patient‐provider relationships, the public's trust in medicine, and medical education. A review of recent survey studies suggests that the clinical use of placebo appears to be fairly well accepted among healthcare professionals and is common in clinical settings in various countries. However, we think that an ethical discussion is urgently needed because of its controversial nature. If judged to be ethically wrong, the practice should end. In the present paper, we discuss the ethicality of the clinical use of placebo with deception and argue against it, concluding that it is unethical and should be banned. We will show that most arguments in favor of the clinical use of placebo can be refuted and are therefore incorrect or weak. These arguments will be presented and examined individually. Finally, we will briefly consider issues relevant to the clinical use of placebo without deception.     

A valid formulation of the analysis of noninferiority trials under random effects meta-analysis

A noninferiority (NI) trial is sometimes employed to show efficacy of a new treatment when it is unethical to randomize current patients to placebo because of the established efficacy of a standard treatment. Under this framework, if the NI trial determines that the treatment advantage of the standard to the new drug (i.e. S-N) is less than the historic advantage of the standard to placebo (S-P), then the efficacy of the new treatment (N-P) is established indirectly. We explicitly combine information from the NI trial with estimates from a random effects model, allowing study-to-study variability in k historic trials. Existing methods under random effects, such as the synthesis method, fail to account for the variability of the true standard versus placebo effect in the NI trial. Our method effectively uses a prediction interval for the missing standard versus placebo effect rather than a confidence interval of the mean. The consequences are to increase the variance of the synthesis method by incorporating a prediction variance term and to approximate the null distribution of the new statistic with a t with k-1 degrees of freedom instead of the standard normal. Thus, it is harder to conclude NI of the new to (predicted) placebo, compared with traditional methods, especially when k is small or when between study variability is large. When the between study variances are nonzero, we demonstrate substantial Type I error rate inflation with conventional approaches; simulations suggest that the new procedure has only modest inflation, and it is very conservative when between study variances are zero. An example is used to illustrate practical issues.     

Is a unified concept of species in ornithology possible? (An opinion of a practicing taxonomist)]

An analysis of current publications on species problem reveals the radical discrepancy between the statements of species reality in nature and different number of these "realities" in light of different species concepts. It has been shown, that the only realities are populations, and "species" is only logical construct--the notion. A concept of species is a system of interconnected notions, where the main element--ontology of species has been always given a priori to the real biodiversity. For that reason every concept of species creates its own "virtual reality". Various concepts of species are not mutually comparable, and can not be criticized from each other's views and from position of "reality". Biological and Phylogenetic Species Concepts competing in ornithology exclude each other completely, and the unified concept of species is principally impossible. But as generally accepted species "standard" is needed, the unified convention of species must take the place of the various concepts of species.     

Introduction to placebo effects in medicine: mechanisms and clinical implications

The field of placebo research has made considerable progress in the last years and it has become a major focus of interest. We know now that the placebo effect is a real neurobiological phenomenon and that the brain's 'inner pharmacy' is a critical determinant for the occurrence of psychobiological and behavioural changes relevant to healing processes and well-being. However, harnessing the advantages of placebo effects in healthcare is still a challenge. The first part of the theme issue summarizes and discusses the various kinds of placebo mechanisms across medical fields, thereby not only focusing on two main explanatory models-expectation and conditioning theory-but also taking into account empathy and social learning, emotion and motivation, spirituality and the healing ritual. The second part of the issue focuses on questions related to transferring knowledge from placebo research into clinical practice and discusses implications for the design and interpretation of clinical trials, for the therapeutic settings in daily patient care, and for future translational placebo research.     

Ethanol induced teratogenesis: characterization, mechanisms and diagnostic approaches

Extensive research has been aimed at characterising FAS and FAE. Whereas the symptomology for FAS has been established, that of FAE remains to be fully characterized. Various mechanisms of ethanol induced teratogenesis have been proposed however it remains to be defined how these mechanisms combine to produce the entire constellation of teratogenic characteristics observed. At present, impaired placental transport, abnormal muscle organogenesis and fetal hypoxia have limitations in explaining the entire spectrum of defects in FAS. The role of prostaglandins and hormones requires further research. Also, other as yet unidentified mechanisms may exist. Even if the composite mechanism can be established, ethanol effects in utero will likely not be preventable by any approach other than consumption modification. In light of this notion, future research into identifying high-risk pregnant drinkers for clinical intervention is emphasized. Intervention leading to abstinence or, if this is not possible, removing the infant as early as possible from an intrauterine environment that is causing growth retardation and fetal distress, are the only solutions available at present.     

Limb,tooth, beak: Three modes of development and evolutionary innovation of form

The standard model of evolutionary change of form, deriving from Darwin’s theory via the Modern Synthesis, assumes a gradualistic reshaping of anatomical structures, with major changes only occurring by many cycles of natural selection for marginal adaptive advantage. This model, with its assertion that a single mechanism underlies both micro- and macroevolutionary change, contains an implicit notion of development which is only applicable in some cases. Here we compare the embryological processes that shape the vertebrate limb bud, the mammalian tooth and the avian beak. The implied notion of development in the standard evolutionary picture is met only in the case of the vertebrate limb, a single-primordium organ with morphostatic shaping, in which cells rearrange in response to signalling centres which are essentially unchanged by cell movement. In the case of the tooth, a single-primordium organ with morphodynamic shaping in which the strengths and relationships between signalling centres is influenced by the cell and tissue movements they induce, and the beak, in which the final form is influenced by the collision and rearrangement of multiple tissue primordia, abrupt appearance of qualitatively different forms (i.e. morphological novelties) can occur with small changes in system parameters induced by a genetic change, or by an environmental factor whose effects can be subsequently canalized genetically. Bringing developmental mechanisms and, specifically, the material properties of tissues as excitable media into the evolutionary picture, demonstrates that gradualistic change for incremental adaptive advantage is only one of the possible modes of morphological evolution.     

Excitation-contraction coupling in the heart: the state of the question.

Recent developments have led to great progress toward determining the mechanism by which calcium is released from the sarcoplasmic reticulum in the heart. The data support the notion of calcium-induced calcium release via a calcium-sensitive release channel. Calcium release channels have been isolated and cloned. This situation creates a paradox, as it has also been found that calcium release is smoothly graded and closely responsive to sarcolemmal membrane potential, properties that would not be expected of calcium-induced calcium release, which has intrinsic positive feedback. There is, therefore, no quantitative understanding of how the properties of the calcium release channel can lead to the macroscopic physiology of the whole cell. This problem could, in principle, be solved by various schemes involving heterogeneity at the ultrastructural level. The simplest of these require only that the sarcolemmal calcium channel be located in close proximity to one or more sarcoplasmic reticulum release channels. Theoretical modeling shows that such arrangements can, in fact, resolve the positive feedback paradox. An agenda is proposed for future studies required in order to reach a specific, quantitative understanding of the functioning of calcium-induced calcium release.     

Complementary methodology in the analysis of rhythmic data, using examples from a complex situation, the rhythmicity of temperature in night shift workers

The methodology for analyzing a biological rhythm has already been the subject of much investigation. However, many questions still have no answer, for example, questions such as the periods chosen: fixed or determined. Throughout this article, we suggest a somewhat innovative methodology that makes it possible to define the steps that seem essential to us in the scientific analysis of rhythms. For some time, this methodology has been put into practice in our laboratory in various studies, some of which have given rise to publications. The notion of quality is a new notion that is present in industry and, when applied to sampling, can improve experimentation. In this way, one may judge the degree to which data samples can be explored as well as the degree of validity of the results of exploration. We provide several methods for achieving this. The search for periods is also important. For this, we have various methods but we must be able to determine those that are the most appropriate and reliable in a particular case. We propose spectral methods, two of which are new and complement 'Cosinor' methodology. On the other hand, modelling uses various methods such as those from, for example, periodic trigonometric functions or more complex chaos functions. We are interested in models from the field of regression (the cosine model) and complementary statistical tests that make it possible to validate the proposed model.     

Meta-analysis of effects and side effects of low dosage tricyclic antidepressants in depression: systematic review

ObjectiveTo compare the effects and side effects of low dosage tricyclic antidepressants with placebo and with standard dosage tricyclics in acute phase treatment of depression.DesignSystematic review of randomised trials comparing low dosage tricyclics (⩽100 mg/day) with placebo or with standard dosage tricyclics in adults with depression.Results35 studies (2013 participants) compared low dosage tricyclics with placebo, and six studies (551 participants) compared low dosage tricyclics with standard dosage tricyclics. Low dosage tricyclics, mostly between 75 and 100 mg/day, were 1.65 (95% confidence interval 1.36 to 2.0) and 1.47 (1.12 to 1.94) times more likely than placebo to bring about response at 4 weeks and 6-8 weeks, respectively. Standard dosage tricyclics failed, however, to bring about more response but produced more dropouts due to side effects than low dosage tricyclics.ConclusionsTreatment of depression in adults with low dose tricyclics is justified. However, more rigorous studies are needed to definitively establish the relative benefits and harms of various dosages.

What is already known on this topic

Tricyclics are still prescribed as often as selective serotonin reuptake inhibitors and other newer antidepressants worldwideExperts have often claimed that clinicians prescribe tricyclics at less than adequate dosages

What this study adds

Tricyclics at dosages below the recommended range are more effective than placeboThey may or may not be as effective as standard dosage tricyclics but result in fewer dropouts due to side effectsThe minimum effective dosage and ranges for antidepressants has not been established—a simple set of numbers that every practising doctor and patient would want to know