循证医学时代安慰剂的再认识

安慰剂的治疗作用早已被人们认识,但是对于其在医学上的应用却一直存在争议.在循证医学兴起的今天,我们应该如何辩证地看待安慰剂的作用及不足,以及在临床试验中应该如何应用安慰剂是一个值得探讨的问题.     

反安慰剂效应在临床试验中的研究

临床工作中,患者在服药后有时会出现一些不良反应,其中有些是由于药物的特殊药理作用导致的,但也有一些属于非特异性的不良反应.近些年来,随着对安慰剂效应研究的逐步深入,人们越来越注意到,“意识”在不良反应的发生中也起到了重要的作用,即反安慰剂效应的作用.本文将从几个不同方面阐述反安慰剂效应的作用及影响因素,并讨论应如何认识、处理临床冶疗和临床试验中反安慰剂效应的问题.     

新药临床试验中安慰剂的使用与伦理思考

新药临床试验中使用安慰剂是一个颇具争议的问题.结合国内外的研究情况,通过具体实例阐述了安慰剂的作用和机理,并讨论如何解决临床试验中与安慰剂设置有关伦理学的问题,旨在为我国临床试验制定相应的指导原则和标准提供参考.     

关于安慰剂效应的研究

安慰剂效应是指由安慰剂所引起的可观察的行为.本文讨论了安慰剂效应的确切定义,安慰剂效应的强度差异,以及临床背景、患者的人格特质、安慰剂的特征和医患关系等因素对安慰剂效应的影响.目前研究者普遍认为安慰剂效应通过期待和条件作用产生.近期的一个研究热点是疼痛和帕金森氏症背景下期待引起的安慰剂效应的神经机制.     

对肾移植输血问题的思考

就肾移植受者输血的几个问题进行了回顾和探讨。提出肾移植受者输血应该考虑的问题有：如何权衡输血对肾移植受者的有益作用与输血风险,输血医学的发展如何为肾移植提供更有力的保障,应该深入探讨输血有益于肾移植的机制,推进供者特异性输血在我国的应用。     

背外侧前额叶在安慰剂效应中的作用：社会情绪调节研究

为考察安慰剂效应在情绪调节中的脑机制,本研究以社会排斥图片为情绪诱发材料诱发社会疼痛,采用经颅磁刺激技术(transcranialmagneticstimulation,TMS)激活背外侧前额叶(dorsolateralprefrontalcortex,DLPFC),并使用事件相关电位观测TMS对安慰剂下调社会疼痛的影响。实验以“TMS组别”(DLPFC组、控制组)为被试间变量,“安慰剂条件”(安慰剂、非安慰剂)为被试内因素。结果发现, DLPFC组(n=50)比控制组(n=50)在安慰剂条件下报告的负性情绪更弱,反映情绪体验强度的晚正成分的波幅也更低,上述组间差异在非安慰剂条件不显著。结果还表明,DLPFC组比控制组更相信安慰剂的效果,愿意花更多的钱来购买安慰剂。此外相关结果发现,由DLPFC激活导致的安慰剂效应增强可有效降低社交焦虑倾向被试的负性社会情绪。本研究是结合脑调控和脑观测技术探讨安慰剂情绪调节脑机制的首次尝试,研究发现不但揭示了DLPFC在安慰剂调节情绪过程中的重要因果作用,还为临床治疗以情绪失调为主要症状的抑郁焦虑等精神障碍患者提供了脑调控干预的可行性脑靶点。     

安慰剂效应研究实验设计的历史和发展

安慰剂处理从最初作为研究某种真实治疗效应的控制条件, 已演变为研究者直接关注的研究目标, 其实验范式也发生了相应变化。双盲随机设计关注真实的治疗是否优于安慰剂处理; 欺骗设计直接比较安慰剂处理效应和自然历史效应的差异, 关注安慰剂效应本身; 公开隐藏设计通过计算公开治疗效应和隐藏治疗效应之差来估计安慰剂效应的大小; 平衡范式可同时观察安慰剂效应和真实治疗效应; 强化范式通过条件性强化获得加强的安慰剂效应, 是研究其作用机制的优化方案; 本课题组建立的迁移强化范式, 研究安慰剂效应从痛觉到情绪的迁移, 是强化范式的重要补充。     

新药临床试验中的反安慰剂效应

新药在临床试验中设立安慰剂对照需要患者知情同意,有违安慰剂暗示治疗的本意。在一种新药Ⅱ期临床试验中,发现告知与隐瞒设立安慰剂对照的事实,疗效差异明显。表明告知患者可能使用到安慰剂,会产生反安慰剂效应,影响疗效判定。提出疗效判定尽量使用客观指标、采用叠加设计、采用暂时隐瞒法、心理医生介入等4项对策。     

对立的双生子:基于疼痛的安慰剂效应和反安慰剂效应机制

心理预期是具有方向性的,可分为正性(积极的)和负性(消极的)预期,它们相互对立,并对人的身心状况产生不同的影响。在长久以来的临床实践中,预期对疾病治疗和某些生理体验的强大调节作用逐渐为人们所知,并根据其调节方向的不同催生出两个重要概念,即安慰剂与反安慰剂效应。目前关于安慰剂与反安慰剂的研究主要集中在疼痛领域。出人意料的是,尽管二者在疼痛调节上具有相似的心理机制,其内在神经基础并不完全相同:安慰剂效应与反安慰剂效应分别由阿片肽系统和胆囊收缩素系统所介导;在影像学研究中,疼痛加工系统和脊髓在安慰剂/反安慰剂的调节下呈现相反的激活模式,而海马在反安慰剂中的活动具有特异性。     

新药临床试验中的反安慰剂效应

新药在临床试验中设立安慰剂对照需要患者知情同意,有违安慰剂暗示治疗的本意.在一种新药Ⅱ期临床试验中,发现告知与隐瞒设立安慰剂对照的事实,疗效差异明显.表明告知患者可能使用到安慰剂,会产生反安慰剂效应,影响疗效判定.提出疗效判定尽量使用客观指标、采用叠加设计、采用暂时隐瞒法、心理医生介入等4项对策.     

Goal activation, expectations, and the placebo effect

Motivational factors receive little attention in current theories of the placebo effect. Reasons for this position are reviewed, and an argument is made for reconsidering the influence of motivation on the placebo effect. The authors hypothesize that nonconscious goals alter reactions to a placebo expectation. Specifically, the authors predict that the placebo effect is most likely to occur when individuals have a goal that can be fulfilled by confirmation of the placebo expectation. The authors tested this notion in 5 experiments. The results demonstrate the role of motivation in the placebo effect across a variety of symptom domains and via 4 different goal activation techniques. Moreover, this moderating effect occurred for both positive and negative placebo expectations, across different placebo effect measures, and in brief laboratory experiments as well as in lengthier studies. It is argued that theories regarding the placebo effect should incorporate motivational factors.     

Placebo effects in developmental disabilities: implications for research and practice

Recent clinical trials of secretin in children with autism showed robust placebo effects and no benefit of secretin over placebo. This article explores the reasons for the observed placebo effects, focusing on the heightening of positive expectancy by media attention and by the sensory experiences associated with intravenous injections. Comparisons are drawn with research involving other novel treatments and other clinical populations of children with developmental disabilities and neurobehavioral disorders. Research regarding mechanisms of placebo effects is reviewed, including patient and clinician attributes, expectancy effects, participation effects, changes in caregiver behavior, and conditioning. New evidence regarding the biological basis of placebo effects is briefly presented. Since placebo effects are ubiquitous and may operate by a variety of mechanisms, research design is critical in designing clinical trials and in evaluating other outcomes research. Measurement issues important for research in developmental disabilities are emphasized. Ethical concerns have been raised regarding the use of placebo in clinical research, but current analysis suggests that placebo controls are necessary and defensible on ethical grounds, if certain conditions are met. The study of placebo effects ("placebology") holds great promise as a new area of research in therapeutics. The author's research in the potential augmentation of stimulant effects in children with attention deficit/hyperactivity disorder (ADHD) by adding placebo in open label is briefly presented. The placebo has always been integral to the practice of medicine, but advances in scientific medicine and medical ethics have diminished the role and use of placebo in practice. An innovative approach to the ethical use of placebo is proposed.     

What it takes to defend deceptive placebo use

A complete defense of deceptive placebo use must address this ethical objection: deceptive placebo use violates patient autonomy, because deceiving a patient about the placebo nature of a proposed treatment prevents her from giving informed consent to the treatment. Unfortunately, this objection isn't always recognized and clearly disambiguated from other ethical concerns. I consider how well several bioethicists who write about placebo use have responded to, or evaded, this objection. I conclude that defenders of deceptive placebo use should, following the lead of Onora O'Neill, argue that deceptive placebo use is compatible with informed consent.     

What You Don't Know Can Help You: The Ethics of Placebo Treatment

Is it permissible for a doctor or nurse to knowingly administer a placebo in a clinical setting? There is certainly something suspicious about it: placebos are typically said to be ‘sham’ treatments, with no ‘active’ properties and so giving a placebo is usually thought to involve tricking or deceiving the patient who expects a genuine treatment. Nonetheless, some physicians have recently suggested that placebo treatments are sometimes the best way to help their patients and can be administered in an honest way. These physicians conclude that placebo treatments are a perfectly acceptable, and ethically unproblematic, mode of treatment. While I grant the common idea that placebos are deceptive is correct, I argue that widespread misunderstandings concerning why this is so has led proponents of placebo treatments to respond to the charge of deception in a way that misses the mark entirely. My goal in this paper, then, is to develop a precise conception of what makes something a placebo, which in turn will clarify the central charge concerning the ethics of placebo treatment, viz. that it is deceptive.     

The placebo effect: dissolving the expectancy versus conditioning debate

The authors review the literature on the 2 main models of the placebo effect: expectancy theory and classical conditioning. A path is suggested to dissolving the theoretical impasse that has long plagued this issue. The key is to make a clear distinction between 2 questions: What factors shape placebo effects? and What learning mediates the placebo effect? The reviewed literature suggests that classical conditioning procedures are one shaping factor but that verbal information can also shape placebo effects. The literature also suggests that conditioning procedures and other sources of information sometimes shape conscious expectancies and that these expectancies mediate some placebo effects; however, in other cases conditioning procedures appear to shape placebo effects that are not mediated by conscious cognition.     

Trait predictors of placebo responses in itch

This study investigated trait predictors of placebo responses in the context of inflammatory skin reactions. This was a randomized, cross-over, experimental study using a deceptive placebo protocol. A healthy sample of volunteers (N = 48) completed online personality measures, then attended two laboratory sessions in which short-term inflammatory skin reactions were induced. One was a control session and the other the ‘treatment’ session in which a placebo cream was administered with the suggestion of a reduced skin reaction. A placebo response was defined as smaller skin reactions in control vs. treatment sessions. The traits ego resiliency and neuroticism were selected as possible predictors of placebo responses. Traits were selected in consideration of the two-faceted transactional model of placebo responsiveness and in light of empirical and psychometric considerations ego resiliency emerged as a consistent predictor of placebo responses in itch (p < .05). This is the first study to identify trait predictors of placebo responses in inflammatory skin reactions. Ego resiliency may typify greater placebo responsiveness; however, this may only be in certain contexts. Matching treatment approaches to bio-behavioural response tendencies may be useful clinically if the placebo component of traditional treatments can be enhanced.     

Treatment Choice and Placebo Expectation Effects

Placebo expectations can have a strong influence on physical and mental health outcomes. In prior research examining placebo expectation effects, participants have been assigned placebo treatments rather than being actively involved in selecting their treatment. In modern health care, however, individuals are often involved in health care decisions. We review relevant literature regarding choice and placebo expectation effects and conclude that exercising choice over a treatment should strengthen placebo effects. Data relevant to this hypothesis is reviewed. Next, we provide a framework for understanding the key variables involved in mediating and moderating the influence of treatment choice on placebo expectation effects. Finally, theoretical and practical issues revolving around treatment choice in the context of placebo effects are raised.     

The Power of Expectation – Understanding the Placebo and Nocebo Phenomenon

Although placebo pills are supposed to have no pharmacological activity, people taking placebo pills describe a variety of positive (i.e., placebo phenomenon) and negative (i.e., nocebo phenomenon) reactions. This has major clinical implications. Placebo reactions account for a substantial part of improvement when treating patients with hypertension, mental disorders, and even after surgical procedures. The nocebo phenomenon on the other hand is responsible for non‐compliance and discontinuation of many pharmaceutical interventions. Mechanisms that underlie the placebo and nocebo effects may be related to expectation and/or classical conditioning, but some methodological issues should also be considered. Most experimental studies investigating the placebo effect have used paradigms to induce ‘placebo analgesia’, the reduction of pain perception after receiving an inert substance and an instruction that this medication would relieve pain. This paradigm allows investigators to examine the neurobiological circuitry of the placebo response using neuroimaging techniques.     

Implications of placebo theory for clinical research and practice in pain management

We review three possible theoretical mechanisms for the placebo effect: conditioning, expectancy and endogenous opiates and consider the implications of the first two for clinical research and practice in the area of pain management. Methodological issues in the use of placebos as controls are discussed and include subtractive versus additive expectancy effects, no treatment controls, active placebo controls, the balanced placebo design, between- versus within-group designs, triple blind methodology and the double expectancy design. Therapeutically, the possibility of shaping negative placebo responses through placebo sag, overservicing and the use of placebos on their own are explored. Suggestions for using conditioned placebos strategically in conjunction with nonplacebos are made and ways of maximizing the placebo component of nonplacebo treatments are examined. Finally, the importance of investigating the placebo effect in its own right is advocated in order to better understand the long-neglected psychological aspects of the therapeutic transaction.     

Motivation and expectancy influences in placebo responding: The mediating role of attention

Drawing upon research in perception and motivation, the current study proposes a motivation‐attention model of placebo in which more motivated persons pay greater attention to placebo‐related stimuli, directly influencing placebo response. We manipulated both motivation to respond to placebo and expectations of placebo response in a 2 × 2 design. Participants (N = 152) evaluated a series of placebo pheromones (slightly scented water) of potential romantic dates and made desirability ratings. Consistent with hypotheses, more highly motivated participants demonstrated greater placebo responses, as evidenced by higher desirability ratings of the “pheromone” and greater variability among ratings, when compared to less motivated participants. Moreover, the relation between motivation and placebo response was mediated by attention. Contrary to expectations, we found no effect for expectancy. These findings highlight the importance of motivation and the mediating factor of attention in placebo and support goal‐oriented models of placebo.