For many years, placebos have been conceptualised by their inert content and their use as controls in clinical trials and treatments in clinical practice. Recent research demonstrates that placebo effects are genuine psychobiological phenomenon attributable to the overall therapeutic context, and that placebo effects can be robust in both laboratory and clinical settings. Evidence has also emerged that placebo effects can exist in clinical practice, even if no placebo is given. Further promotion and integration of laboratory and clinical research will allow advances in the ethical harnessing of placebo mechanisms that are inherent in routine clinical care and the potential use of treatments to primarily promote placebo effects.
There are no prospective, multicenter double-blind placebo-controlled randomized pharmacological trials for the treatment of pain predominant functional GI disorders in children.
Evaluate the efficacy of amitriptyline in children with pain predominant functional GI disorders.
Multicenter placebo-controlled trial. Children with irritable bowel syndrome, functional abdominal pain or functional dyspepsia were randomized to 4 weeks of placebo or amitriptyline (10 mg/d <35 kg; 20 mg/d >35 kg). Assessment of GI symptoms, psychological traits and daily activities before and after intervention. Pain was assessed daily with self-report diaries. Primary outcome: overall response to treatment (child's assessment of pain relief and sense of improvement). Secondary outcomes: effect on psychosocial traits and daily functioning.
90 children enrolled, 83 completed the study (placebo: 40, 30 females; drug: 43, 35 females). Patients reported feeling better 63%, worse 5% in amitriptyline arm vs. better 57.5%, worse 2.5% in placebo arm (p=0.63). Pain relief was excellent (7%), good (38%) in children on placebo and excellent (15%), good (35%) in amitriptyline (p=0.85). Logistic regression analysis of those reporting excellent or good response vs. fair, poor or failed showed no difference between amitriptyline and placebo (p=0.83). Children who had more severe pain at baseline in both groups (p=0.0065) had worse outcome. Amitriptyline reduced anxiety scores (p<0.0001).
Both amitriptyline and placebo were associated with excellent therapeutic response. There was no significant difference between amitriptyline and placebo after 4 weeks of treatment. Patients with mild to moderate intensity of pain responded better to treatment.
This paper addresses the role of paracetamol in placebo-controlled osteoarthritis (OA) trials and the potential contribution to the large placebo response in such trials. Paracetamol is used as rescue medication in nearly all OA placebo-controlled trials. Triggered by the discussion about the placebo effect in general and because of the lack of systematic reviews of placebo effect in OA trials, a recent meta-analysis examined the placebo effect and its potential determinants in the treatment of OA, as the main result came out that placebo is very effective in the treatment of OA, especially for pain, stiffness, and self-reported function. However, mostly limited data are available from published OA trials on the starting dose, final dose, dose over time of paracetamol use, and the percentage of patients who used rescue medication during the study. Paracetamol may be an important additional simulated effect of placebo administration mimicking the true placebo effect and thus a missing link contributing partially to the large placebo response in OA trials. Therefore, the positive effect of paracetamol on symptom relief as well as the need for standardized recording of rescue medication should be taken into account when designing, executing, and interpreting placebo-controlled OA studies.
Placebo analgesic effects appear to be related to patients' perception of the therapeutic intervention. In this paper, we review quantitative findings of how the relationship with the physician and the verbal suggestions given for relief may influence patients' perception of a treatment and how patients' expectations and emotional feelings may affect treatment outcome. We also present qualitative data from interviews with patients who have experienced pain relief following a placebo or an active treatment. A special focus is given to the temporal development of placebo analgesia at psychological and neurophysiological levels. Finally, we discuss the extent to which the quantitative and qualitative findings supplement or contrast with each other, and we touch upon possible implications of patients' direct experience as central for placebo analgesia.
placebo analgesia; patient–physician relationship; verbal suggestions; expectations; emotional feelings; temporal development
Placebo therapy has always been a subject of controversy in the field of medicine. Some choose to admit it as “fake, irresponsible medicine” while others advocate its effectiveness in various clinical settings. With the advent of the recent concept of mind-body medicine, placebo has entered from fringe to mainstream therapeutics. Some clinicians use it for its actual positive outcomes while others use it merely to buy time until definitive diagnosis or even as a pacifier for patients.
The present study was carried out to observe the perceptions about placebo therapy among health practitioners in Jazan region of Saudi Arabia
Data was analyzed through statistical analysis of retrospective questionnaires addressing various issues on placebo therapy, including types of placebo used in various clinical settings, mechanism of placebo action, ethics of use and openness with patients etc.
The study elucidated that the perceptions regarding placebo therapy are subjective and variable within and between institutions ranging from firm belief in its positive effects and efficacy; to neutral attitudes among some, to strong opposition for it among still others.
More research is needed to ethically define the boundary between explicit fraudulence and marginalized evidence based therapeutic deception to effectively achieve the goal of positive health outcomes in patients.
Placebo therapy; Saudi Arabia
In recent years, the placebo effect has been a topic of considerable interest both in the scientific and the clinical community. In this time, the placebo effect has evolved from being considered a nuisance in clinical and pharmacological research to becoming a neurobiological phenomenon worthy of scientific investigation in its own right. Recent research shows that placebo effects are genuine psychobiological events attributable to the overall therapeutic context, and that these effects can be robust in both laboratory and clinical settings. These psychosocially induced biochemical changes in a patient's brain and body may in turn affect the course of a disease and the response to a therapy. Here we summarize and discuss the current insights into placebo mechanisms and discuss the potentially widespread implications for research and clinical practice. Even though a systematic knowledge of placebo effects across the lifespan is lacking, we aim at highlighting specific aspects related to the care of elderly patients and those suffering from neurodegenerative diseases.
Placebo; Nocebo; Neurobiology; Placebo effect, clinical implications; Aging
Current evidence supports the efficacy of placebo analgesia and illustrates that patients may be open to placebo use despite uncertainty regarding its mechanisms. Debate persists, however, concerning the ethics of placebo treatments. The purpose of the present web-based study was to expand upon the empirical literature on placebo analgesia ethics and acceptability. Participants (n = 100) provided their definition of a placebo and responded to 24 questions addressing placebo analgesia perceived knowledge, acceptability, effectiveness, and likelihood of placebo use among different healthcare providers. Results support previous research on the effects of placebo on negative mood and healthcare provider attributions, with findings illustrating that negative consequences of administration were largely mitigated by a beneficial treatment outcome. Results showed that participants conceptualized placebo as predominately “inert” and were mixed regarding interpretations of placebo effectiveness. Though acceptability ratings were dependent on the context of placebo administration, participants endorsing even moderate placebo acceptability were more open to placebo interventions and reported overall more positive treatment outcomes. Participants believed that placebos were used differentially among healthcare providers. Additional studies are needed to determine if placebo education can beneficially impact perceptions of placebo analgesia knowledge, acceptability, and treatment effectiveness.
Placebo analgesia; placebo acceptability; placebo ethics; placebo knowledge; placebo treatment
Recent research into the placebo effect has implications for the ethics of shared decision-making (SDM). The older biomedical model views SDM as affecting which therapy is chosen, but not the nature or likelihood of any health outcomes produced by the therapy. Research indicates, however, that both the content and manner in which information is shared with the patient, and the patient’s experience of being involved in the decision, can directly alter therapeutic outcomes via placebo responses. An ethical tension is thereby created between SDM aimed strictly and solely at conveying accurate information, and “outcome engineering” in which SDM is adapted toward therapeutic goals. Several practical strategies mitigate this tension and promote respect for autonomous decision-making while still utilizing the therapeutic potential of SDM.
In a randomised placebo-controlled clinical trial it is assumed that psychosocial effects of the treatment, regression to the mean and spontaneous remission are identical in the drug and placebo group. Consequently, any difference between the groups can be ascribed to the pharmacological effects. Previous studies suggest that side effects of drugs can enhance expectancies of treatment effects in the drug group compared to the placebo group, and thereby increase placebo responses in the drug group compared to the placebo group.
The hypothesis that side effects of drugs can enhance expectancies and placebo responses was tested.
Painful laser stimuli were delivered to 20 healthy subjects before and after administration of a drink with 0 or 4 mg/kg caffeine. The drink was administered either with information that it contained a painkiller or that it was a placebo. Laser-evoked potentials and reports of pain, expectancy, arousal and stress were measured.
Four milligrammes per kilogramme of caffeine reduced pain. Information that a painkiller was administered increased the analgesic effect of caffeine compared to caffeine administered with no drug information. This effect was mediated by expectancies. Information and expectancies had no effect on pain intensity when 0 mg/kg was administered.
The analgesic effect of caffeine was increased by information that a painkiller was administered. This was due to an interaction of the pharmacological action of the drug and expectancies. Hence, psychosocial effects accompanying a treatment can differ when an active drug is administered compared to a placebo.
Placebo analgesia; Pain; Expectancies; Laser-evoked potentials; Active placebo; Caffeine; Arousal; Balanced placebo design
The placebo effect, a positive outcome resulting from the belief that a beneficial treatment has been received, is widely acknowledged but little understood. It has been suggested that placebo responsiveness, the degree to which an individual will respond to a placebo, might vary in the population. The study aimed to identify placebo-responsive participants from a previously published paper that examined the effects of caffeine and placebos on cycling performance. A quantitative model of placebo responsiveness was defined. 14 male participants were subsequently classified as either placebo responsive or non-responsive. Interviews were conducted to corroborate these classifications. Secondary quantitative analyses of performance data were conducted to identify further placebo responses. Finally, the five factor model of personality was used to explore relationships between personality and placebo responsiveness. Overall, 5 of 14 participants were classified as placebo responsive. Performance data suggested that 2 participants were placebo responsive whilst 12 were not. Interview data corroborated experimental data for these participants and for 9 of the remainder, however it suggested that the remaining 3 had experienced placebo effects. Secondary quantitative analysis revealed that performance for these 3 participants, whilst no better than for non-responsive participants, was associated with substantially increased oxygen uptake in the 2 conditions in which participants believed caffeine had been administered (7.0% ± 15.1; 95% confidence intervals -2.6 to 16.7, and 6.0% ± 15.4; -3.9 to 15.9 respectively). Finally, data suggested that the personality factors of extroversion, agreeableness, openness and neuroticism may relate to placebo responding. Placebo effects such as pain tolerance and fatigue resistance might be experienced by a percentage of participants but might not always be manifest in objective measures of performance.
Beliefs can have both positive (placebo) and negative (nocebo) effectsPlacebo effects may be experienced both objectively and subjectivelyCertain personality traits may be related to placebo respondingA multi-method approach may best elucidate placebo effects in sport.
Caffeine; personality; placebo effect; nocebo effect; qualitative
Investigations of the effect of placebo are often challenging to conduct and interpret. The history of placebo shows that assessment of its clinical significance has a real potential to be biased. We analyse and discuss typical types of bias in studies on placebo.
STUDY DESIGN AND SETTING
a methodological analysis and discussion.
The inherent nonblinded comparison between placebo and no-treatment is the best research design we have in estimating effects of placebo, both in a clinical and in an experimental setting, but the difference between placebo and no-treatment remains an approximate and fairly crude reflection of the true effect of placebo interventions. A main problem is response bias in trials with outcomes that are based on patients reports. Other biases involve differential co-intervention and patient drop-outs, publication bias, and outcome reporting bias. Furthermore, extrapolation of results to a clinical settings are challenging because of lack of clear identification of the causal factors in many clinical trials, and the non-clinical setting and short duration of most laboratory experiments.
Creative experimental efforts are needed to assess rigorously the clinical significance of placebo interventions and investigate the component elements that may contribute to therapeutic benefit.
Placebo; placebo effect; response bias; bias; randomised trial; experiment
In medical research, the
placebo effect is an important
methodological tool. Placebo is
given to participants in clinical
trials, with the intention of
mimicking an experimental
intervention. The "nocebo" effect,
on the other hand, is the phenomenon
whereby a patient who believes
that a treatment will cause harm
actually does experience adverse
effects. The placebo effect strongly
influences the way the results of
clinical trials are interpreted.
Placebo responses vary with the
choice of study design, the choice
of primary outcome measure, the
characteristics of the patients and
the cultural setting in which the
trial is conducted. In migraine
trials, the placebo response is high,
in terms of both efficacy and side
effects. Although medical ethics
committees are becoming increasingly
resistant to the use of placebo
in acute migraine trials, placebo
nevertheless remains the pivotal
comparator in trials of migraine
Placebo; Migraine; Triptans; NSAIDs; Nocebo
The mechanisms through which manual therapy inhibits musculoskeletal pain are likely multifaceted and related to the interaction between the intervention, the patient, the practitioner, and the environment. Placebo is traditionally considered an inert intervention; however, the pain research literature suggests that placebo is an active hypoalgesic agent. Placebo response likely plays a role in all interventions for pain and we suggest that the same is true for the treatment effects associated with manual therapy. The magnitude of a placebo response may be influenced by negative mood, expectation, and conditioning. We suggest that manual therapists conceptualize placebo not only as a comparative intervention, but also as a potential active mechanism to partially account for treatment effects associated with manual therapy. We are not suggesting manual therapists include known sham or ineffective interventions in their clinical practice, but take steps to maximize placebo responses to reduce pain.
Placebo; Pain; Manual therapy
Analgesia is particularly susceptible to placebo responses. Recent studies in humans have provided important insights into the neurobiology underlying placebo-induced analgesia. However, human studies provide incomplete mechanistic explanations of placebo analgesia because of limited capacity to use cellular, molecular, and genetic manipulations. To address this shortcoming, we describe here the development of a rat model of conditioned analgesia in an operant pain assay. Specifically, rats were conditioned to associate a placebo manipulation with the analgesic effect of 1 mg/kg morphine (s.c.) on facial thermal pain. We found that conditioned (placebo) responding bore three of the hallmarks of placebo-induced analgesia: (1) strong inter-animal variability in the response, (2) suppression by the opiate antagonist naloxone (5 mg/kg, s.c.), and (3) a positive predictive relationship between the unconditioned analgesic effect and the conditioned (placebo) effect. Due to the operant nature of the assay and the use of only a mild noxious thermal stimulus, we suggest these results provide evidence of placebo-induced analgesia in a preclinical model that utilizes an affective behavioral endpoint. This finding may provide opportunities for invasive preclinical studies allowing greater understanding of placebo-induced analgesia, thus paving the way for avenues to harness its benefits.
placebo; operant; analgesia; morphine; opioid; preclinical
Placebo treatment may affect multiple components of pain, including inhibition of nociceptive input, automatic or deliberative appraisal of pain, or cognitive judgments involved in pain reporting. If placebo analgesia is due in part to an attenuation of early nociceptive processing, then pain-evoked event-related potentials (ERPs) should be reduced with placebo. In this study, we tested for placebo effects in P2 laser-evoked potentials at midline scalp electrodes. We found that placebo treatment produced significant decreases in P2 amplitude, and that P2 placebo responses were large enough to reflect a meaningful difference in nociceptive processing. However, we also found evidence that the very robust placebo-induced decreases in reported pain are not solely explained by early reductions in P2. N2 amplitude was affected by neither placebo nor reduction of laser intensity. These results suggest that placebo treatment affects early nociceptive processing, but that another component of placebo effects in reported pain occurs later, either in evaluation of pain or cognitive judgments about pain reports.
Placebo; Laser; Pain; EEG; ERP; LEP; P2; Evoked potentials; Placebo effect
Assumptions underlying placebo controlled trials include that the placebo effect impacts on all study arms equally, and that treatment effects are additional to the placebo effect. However, these assumptions have recently been challenged, and different mechanisms may potentially be operating in the placebo and treatment arms. The objective of the current study was to explore the nature of placebo versus pharmacological effects by comparing predictors of the placebo response with predictors of the treatment response in a randomised, placebo-controlled trial of a phytotherapeutic combination for the treatment of menopausal symptoms. A substantial placebo response was observed but no significant difference in efficacy between the two arms.
A post hoc analysis was conducted on data from 93 participants who completed this previously published study. Variables at baseline were investigated as potential predictors of the response on any of the endpoints of flushing, overall menopausal symptoms and depression. Focused tests were conducted using hierarchical linear regression analyses. Based on these findings, analyses were conducted for both groups separately. These findings are discussed in relation to existing literature on placebo effects.
Distinct differences in predictors were observed between the placebo and active groups. A significant difference was found for study entry anxiety, and Greene Climacteric Scale (GCS) scores, on all three endpoints. Attitude to menopause was found to differ significantly between the two groups for GCS scores. Examination of the individual arms found anxiety at study entry to predict placebo response on all three outcome measures individually. In contrast, low anxiety was significantly associated with improvement in the active treatment group. None of the variables found to predict the placebo response was relevant to the treatment arm.
This study was a post hoc analysis of predictors of the placebo versus treatment response. Whilst this study does not explore neurobiological mechanisms, these observations are consistent with the hypotheses that 'drug' effects and placebo effects are not necessarily additive, and that mutually exclusive mechanisms may be operating in the two arms. The need for more research in the area of mechanisms and mediators of placebo versus active responses is supported.
International Clinical Trials Registry ISRCTN98972974.
Placebo analgesia is being increasingly appraised as an effective support of pharmacological and surgical treatments of pain. The understanding of its neurobiological and psychological basis is therefore of high clinical relevance. It has been shown that placebo analgesia is somatotopically organized and relies on endogenous opioids. However, it is not clear whether temporal fluctuations of cue-dependent spatial attention account for the site specificity of placebo analgesia or whether a somatotopic placebo effect is possible without an attentional focus on the respective location. To address this issue we induced placebo expectations for one specific foot in healthy subjects, the other foot serving as a control location. The feet were stimulated in random order by painful laser stimuli. Half of the pulses were cued for stimulus location, whereas in the other half of trials the subjects were naïve about the location. We found that about half of the subjects exhibited a somatotopic placebo effect that was statistically independent of the spatial cue. We suggest that, after the induction of an initial expectation, placebo analgesia is spatially specific but does not necessarily depend on momentary fluctuations of spatial attention. This result rather suggests that the somatotopy of placebo analgesia relies on the creation of spatially guided expectations or conditioning, but can be maintained without ongoing monitoring of the affected body part.
placebo analgesia; spatial attention; somatotopy
Placebo-controlled randomized trials for antidepressants and other drugs often show a response for a sizeable percentage of the subjects in the placebo group. Potential placebo responders can be assumed to exist also in the drug treatment group, making it difficult to assess the drug effect. A key drug research focus should be to estimate the percentage of individuals among those who responded to the drug who would not have responded to the placebo (”Drug Only Responders”). This paper investigates a finite mixture model approach to uncover percentages of up to four potential mixture components: Never Responders, Drug Only Responders, Placebo Only Responders, and Always responders. Two examples are used to illustrate the modeling, a twelve-week antidepressant trial with a continuous outcome (Hamilton D score) and a 7-week schizophrenia trial with a binary outcome (illness level). The approach is formulated in casual modeling terms using potential outcomes and principal stratification. Growth mixture modeling (GMM) with maximum-likelihood estimation is used to uncover the different mixture components. The results point to the limitations of the conventional approach of comparing marginal response rates for drug and placebo groups. It is useful to augment such reporting with the GMM estimated prevalences for the four classes of subjects and the Drug Only Responder drug effect estimate.
This article reviews the role of placebo interventions and placebo effects in clinical practice. We first describe the relevance of different perspectives among scientists, physicians and patients on what is considered a placebo intervention in clinical practice. We then summarize how placebo effects have been investigated in randomized controlled trials under the questionable premise that such effects are produced by placebo interventions. We further discuss why a shift of focus from the placebo intervention to the overall therapeutic context is necessary and what research methods can be used for the clinical investigation of the relevance of context effects. In the last part of the manuscript, we discuss why placebo or context effects are seen as positive in clinical practice when they are associated with active treatments, while placebo interventions pose major ethical and professional problems and have to be avoided.
clinical practice; placebo; placebo effects; randomized controlled trials; ethics
Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT), an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional val158met polymorphism, was a predictor of placebo effects and tested our hypothesis in a subset of 104 patients from a previously reported randomized controlled trial in irritable bowel syndrome (IBS). The three treatment arms from this study were: no-treatment (“waitlist”), placebo treatment alone (“limited”) and, placebo treatment “augmented” with a supportive patient-health care provider interaction. The primary outcome measure was change from baseline in IBS-Symptom Severity Scale (IBS-SSS) after three weeks of treatment. In a regression model, the number of methionine alleles in COMT val158met was linearly related to placebo response as measured by changes in IBS-SSS (p = .035). The strongest placebo response occurred in met/met homozygotes treated in the augmented placebo arm. A smaller met/met associated effect was observed with limited placebo treatment and there was no effect in the waitlist control. These data support our hypothesis that the COMT val158met polymorphism is a potential biomarker of placebo response.
Objective To investigate whether placebo effects can experimentally be separated into the response to three components—assessment and observation, a therapeutic ritual (placebo treatment), and a supportive patient-practitioner relationship—and then progressively combined to produce incremental clinical improvement in patients with irritable bowel syndrome. To assess the relative magnitude of these components.
Design A six week single blind three arm randomised controlled trial.
Setting Academic medical centre.
Participants 262 adults (76% women), mean (SD) age 39 (14), diagnosed by Rome II criteria for and with a score of ≥150 on the symptom severity scale.
Interventions For three weeks either waiting list (observation), placebo acupuncture alone (“limited”), or placebo acupuncture with a patient-practitioner relationship augmented by warmth, attention, and confidence (“augmented”). At three weeks, half of the patients were randomly assigned to continue in their originally assigned group for an additional three weeks.
Main outcome measures Global improvement scale (range 1-7), adequate relief of symptoms, symptom severity score, and quality of life.
Results At three weeks, scores on the global improvement scale were 3.8 (SD 1.0) v 4.3 (SD 1.4) v 5.0 (SD 1.3) for waiting list versus “limited” versus “augmented,” respectively (P<0.001 for trend). The proportion of patients reporting adequate relief showed a similar pattern: 28% on waiting list, 44% in limited group, and 62% in augmented group (P<0.001 for trend). The same trend in response existed in symptom severity score (30 (63) v 42 (67) v 82 (89), P<0.001) and quality of life (3.6 (8.1) v 4.1 (9.4) v 9.3 (14.0), P<0.001). All pairwise comparisons between augmented and limited patient-practitioner relationship were significant: global improvement scale (P<0.001), adequate relief of symptoms (P<0.001), symptom severity score (P=0.007), quality of life (P=0.01).Results were similar at six week follow-up.
Conclusion Factors contributing to the placebo effect can be progressively combined in a manner resembling a graded dose escalation of component parts. Non-specific effects can produce statistically and clinically significant outcomes and the patient-practitioner relationship is the most robust component.
Trial registration Clinical Trials NCT00065403.
A burgeoning body of evidence supports the efficacy and elucidates the mechanisms of placebo analgesia. Debate persists, however, concerning their ethical use, with many of the present arguments being philosophically-based. The present web-based study empirically investigated the acceptability of an analgesic placebo treatment. Participants (103) responded to vignettes depicting patients receiving a placebo analgesic. We experimentally manipulated 1) placebo treatment instructions (level of deception), 2) treatment outcome, and 3) patients’ pain severity. Participants rated vignettes on outcome measures of deception, physician-patient relationship, and patient mood. Participants then characterized a range of placebo acceptability through ratings of deceptiveness, effectiveness, and negative consequences. Results showed that placebos described as “medication shown to be a powerful analgesic in some people” were equally deceptive as those described as “standard drug treatment.” Ratings of patient mood and physician approval were determined as much by treatment instruction as by treatment outcome and an analgesic response mitigated the negative consequences of deceptive administration. Participants tolerated moderate effectiveness and considerable negative consequences in an acceptable placebo, although results suggest lay individuals may not have a sophisticated conceptualization of placebo effectiveness. Studies altering individuals’ understanding of placebo effectiveness and mechanisms are needed to identify additional factors determining placebo acceptability.
Placebo Acceptability; Analgesia; Ethics
The use of placebo as a control condition in clinical trials of major depressive disorder and anxiety disorders continues to be an area of ethical concern. Typically, opponents of placebo controls argue that they violate the beneficent-based, “best proven diagnostic and therapeutic method” that the original Helsinki Declaration of 1964 famously asserted participants are owed. A more consequentialist, oppositional argument is that participants receiving placebo might suffer enormously by being deprived of their usual medication(s). Nevertheless, recent findings of potential for suicidality in young people treated with antidepressants, along with meta-analyses suggesting that antidepressants add no significant clinical benefit over placebos, warrant a re-evaluation of the arguments against placebo. Furthermore, the nature of placebo treatment in short-term clinical trials is often not well understood, and lack of understanding can foster opposition to it. This paper will show how scientific justifications for placebo use are morally relevant. The fundamental ethical importance of placebo controls is discussed in relation to several aspects of clinical trials, including detection of adverse events, accurate assessment of clinical benefit, advancing understanding of the heterogeneity of depression and anxiety disorders and respecting informed consent requirements. Prohibiting the use of placebo controls is morally concerning in that such prohibitions allow for the possibility of serious adverse public health consequences. Moral worries that research participants receiving placebo are being unduly jeopardised will be shown to be exaggerated, especially in relation to the net benefits for end-users to be gained from the quality of data resulting from using placebo controls.
This paper challenges the common assumption that the mechanisms underlying short-term placebo paradigms (where there is no motivation for health improvement) and long-term placebo paradigms (where patients value improvement in their health) are the same. Three types of motivational theory are reviewed: (i) classical placebo motivation theory that the placebo response results from the desire for therapeutic improvement; (ii) goal activation model that expectancy-driven placebo responses are enhanced when the placebo response satisfies an activated goal; and (iii) motivational concordance model that the placebo response is the consequence of concordance between the placebo ritual and significant intrinsic motives. It is suggested that current data are consistent with the following theory: response expectancy, conditioning and goal activation are responsible for short-term placebo effects but long-term therapeutic change is achieved through the effects of goal satisfaction and affect on the inflammatory response system and hypothalamic–pituitary–adrenal axis. Empirical predictions of this new theory are outlined, including ways in which placebo effects can be combined with other psychologically mediated effects on short-term and long-term psychological and physiological state.
placebo; motivation; clinical; expectancy; psychoneuroimmunology; review
With its naturally fluctuating course, depression is a highly placebo-responsive condition: mean placebo response rates in antidepressant clinical trials are 30% to 40%. We review the history and terminology of placebo and the proposed mechanisms underlying the placebo response, including the physician-patient relationship and biological, sociocultural, and treatment situation factors. We identify the predictors and patterns of placebo response in depressed patients, both within and outside of the clinical trial context, and differentiate between true drug response and placebo pattern response. We discuss the strategies now being advanced to minimize the placebo response given the increased placebo drift reported in recent trials, and the ethical guidelines governing placebo administration. Potential areas for future research include the identification of biological markers of placebo response, such as functional neuroimaging and quantitative electroencephalography, the development and testing of more sophisticated, alternative research designs, and the design of valid biological tools to assess antidepressant efficacy.
placebo; placebo pattern response; true drug response; depression; clinical trials