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PubMed2005

[Determination of placebo effect in irritable bowel syndrome].

BACKGROUND AND OBJECTIVE: The determinants of the placebo effect are not well established. Goal of this study was to explore likely predictive factors in an already published data set. METHODS: We re-analysed data from a study in 120 patients with the irritable bowel syndrome (IBS) that were randomly assigned to three arms of the study to receive (double-blind) either a drug (mebeverin) (n = 40) or placebo (n = 40), or (in an open trial) dietary treatment (fibre) (n = 40) for up to 16 week. Treatment was conducted by 3 different doctors (A, B, C) with 44, 27, and 18 patients, resp. A fourth group (n = 31) was treated by different varying physicians. Symptoms were assessed every 4 weeks, and the degree of patient compliance and the number of drop-outs, the number of patients improved/not improved (in %), symptom severity (Kruis Score) at enrolment, and age and gender as covariates were included into the analysis. RESULTS: Drop-out rate was 30 % for placebo, 30 % for mebeverin, and 15 % for the diet. For the patients remaining in the study, average compliance was 75 % with placebo, but 89 % for the drug and 82 % for the diet. Response rates were 39 % for placebo, but 20 % for the drug; response rate for the diet (open trial) was 43 % under all doctors. Response rates for drug and placebo combined were 32 % for doctor A (female,43 years), but 19 % for doctors B and C together (both males, 32 and 40 years)); this effect was not significant. Placebo responders were more often women (47 %) than men (28 %), while age effects were only found with dietary treatment: responders were younger. Placebo responders had an overall lower Kruis Score than non-responders (45 vs 52 points), but this was also true for drug (52 vs. 62 points) and diet responders (56 vs 68 points). CONCLUSION: The major factors contributing to the placebo response are the treating physician (gender, training), and the patients gender (female). Patients with lower Kruis score (more likely non-functionally disordered) may be prone to higher (placebo) response rates.

Adult↗
PubMed2003

Oral dexamethasone for the treatment of pain in children with acute pharyngitis: a randomized, double-blind, placebo-controlled trial.

STUDY OBJECTIVE: We compare oral dexamethasone with placebo for the relief of pain in children with acute pharyngitis. METHODS: We performed a prospective, randomized, double-blind, placebo-controlled trial of children aged 5 to 16 years who presented to the emergency department with acute pharyngitis. Children rated their pain on a standardized color analog scale and had a rapid streptococcal antigen detection test performed to determine group assignment. Children were randomized to dexamethasone (0.6 mg/kg, maximum dose 10 mg) or placebo. Blinded research assistants called all families daily to determine pain scores until the point of complete pain relief. The primary outcome measures were the time to clinically significant pain relief and the time to complete pain relief. RESULTS: A total of 184 children were enrolled in the study. There were 85 children in the antigen-positive group, of whom 45 were randomized to dexamethasone and 40 to placebo. In children with group A beta-hemolytic streptococcal pharyngitis, the median time to clinically significant pain relief was 6 hours in the dexamethasone group versus 11.5 hours in the placebo group (P =.02; effect size of 5.5 hours with 95% confidence interval [CI] of 1.0 and 10.0 hours), and the time to complete pain relief was similar (36 hours for placebo versus 40 hours for dexamethasone, P =.86; effect size of 4.0 hours with 95% CI of -9.3 and 17.3 hours) in the placebo group. There were 99 children enrolled in the antigen-negative group, of whom 47 received dexamethasone and 52 received placebo. In this group, the median time to clinically significant pain relief was 13 hours in the dexamethasone group versus 9 hours in the placebo group (P =.32; effect size of 4 hours with 95% CI of -2 and 10 hours), and the time to complete pain relief was similar (48 hours for placebo versus 50 hours for dexamethasone, P =.61; effect size of 2 hours with 95% CI of -11.8 and 15.8 hours). CONCLUSION: For all children with acute pharyngitis, oral dexamethasone does not decrease the time to onset of clinically significant pain relief or time to complete pain relief. However, in the subset of children with positive antigen detection test results, there is a statistically significant improvement in time to onset of pain relief, but it is of marginal clinical importance.

Acute Disease↗
PubMed2003

Placebo effects in oncology.

BACKGROUND: Previous studies have suggested that placebo treatment can have positive effects on a variety of disorders and disease-related symptoms. However, the methodology used to collect and interpret the data may not have been ideal, because the studies were not double-blinded or the endpoints were not properly validated. The purpose of the present study was to determine the probability of improvement in symptoms or quality of life and tumor response in cancer patients treated with placebos in randomized controlled trials. We hypothesized that administration of placebos would improve symptom control and quality of life but would not lead to tumor response. METHODS: We reviewed reports of randomized controlled trials in which there was a placebo arm (37 trials) or a best supportive care (BSC) arm (10 trials). RESULTS: In trials that assessed average responses for patients in the placebo arm, improvements in average levels of pain were reported in two of six trials and in appetite, in one of seven trials. No improvements in average levels of weight gain (six trials), in quality of life (as assessed by patients; 10 trials), or in performance status (as assessed by physicians; nine trials) were reported. In trials that assessed response to a placebo in individual patients, 0%-21% of patients showed reduced pain or decreased analgesic intake, 8%-27% of patients showed appetite improvement, 7%-17% of patients showed weight gain, and 6%-14% of patients showed improvement in performance status. Quality of life for individual patients was not reported in any trial. Tumor response assessed by World Health Organization criteria was observed in 10 (2.7%) of 375 patients (seven trials total). Response as assessed by a serum marker was observed in 1 (1.7%) of 60 patients (two trials total). The probability of symptom improvement in patients receiving BSC was generally similar to that in patients receiving placebo, although no improvement in pain and only one tumor response among 191 patients (five trials) were reported. CONCLUSION: In randomized double-blinded, placebo-controlled trials, presumably with minimum sources of bias, placebos are sometimes associated with improved control of symptoms such as pain and appetite but rarely with positive tumor response. Substantial improvements in symptoms and quality of life are unlikely to be due to placebo effects.

Antineoplastic Agents↗
PubMed2006

Direct comparison of placebo effects on clinical and experimental pain.

OBJECTIVES: Placebo effects have been suggested to be more potent on clinical than experimental pain. However, this proposition is based on the comparison of the magnitude of placebo analgesia between studies using different methodologies or between different groups of subjects within the same study. The authors sought to provide a more direct test of this hypothesis using a within-subject design and to investigate the potential mediating effect of expectancy. METHOD: Sixteen patients with low back pain rated the intensity and the unpleasantness of their clinical pain and underwent two cold pressor tests, both before and after a saline injection presented either as a potent painkiller (placebo treatment) in one session or as an inactive substance in a control session. RESULTS: The placebo treatment produced comparable increases in expected relief for clinical and experimental pain. However, ratings of pain intensity, pain unpleasantness, and perceived relief confirmed the larger placebo effect in low back pain than cold pressor pain. Retrospective ratings of perceived relief in low back pain generally showed the largest placebo effect compared with concurrent pain ratings. Furthermore, when the placebo session was performed after the control session, the placebo effect on low back pain was substantially reduced and observed only in perceived relief. Variations in expectation could not account for the large difference in placebo analgesia between clinical and experimental pain. CONCLUSIONS: The important reduction in placebo analgesia in low back pain after the single pre-exposure to the ineffective control treatment suggests the additional involvement of highly flexible mechanisms that may counteract the pro-analgesic effects of expectations.

Adolescent↗
PubMed2005

An internet-based randomized, placebo-controlled trial of kava and valerian for anxiety and insomnia.

The herbal extracts kava and valerian are the leading dietary supplements used in the self-management of anxiety and insomnia, respectively. There is limited evidence to support their effectiveness for these common symptoms. The Internet has been used to a limited extent for research, but it is not known whether randomized controlled trials can be conducted entirely using Internet technology. We performed a randomized, double-blind, placebo-controlled trial using a novel Internet-based design to determine if kava is effective for reducing anxiety and if valerian is effective for improving sleep quality. E-mail recruitment letters and banner advertisements on websites were used to recruit a large pool of interested participants (1551) from 45 states over an 8-week period. Participants were first asked to read study information, complete an online informed consent process, and undergo electronic identity verification. In order to be eligible for the study, participants were required to have 1) anxiety as documented by scores of at least 0.5 standard deviations above the mean on the State-Trait Anxiety Inventory State subtest (STAI-State) on 2 separate occasions, and 2) insomnia, defined as a "problem getting to sleep or staying asleep over the past 2 weeks." We randomly assigned 391 eligible participants to 1 of the following 3 groups, and mailed 28 days' supply: kava with valerian placebo (n = 121), valerian with kava placebo (n = 135), or double placebo (n = 135). The primary outcome measures were changes from baseline in anxiety (STAI-State questionnaire) and insomnia (Insomnia Severity Index [ISI]) compared with placebo. Participants receiving placebo had a 14.4 point decrease in anxiety symptoms on the STAI-State score and an 8.3 point decrease in insomnia symptoms on the ISI. Those receiving kava had similar reductions in STAI-State score (2.7 point greater reduction in placebo compared with kava; 95% confidence interval [CI], -0.8 to +6.2). Those receiving valerian and placebo had similar improvements in sleep (0.4 point greater reduction in the placebo than the valerian group; 95% CI, -1.3 to +2.1). Results were similar when limited to the 83% of participants who adhered to study compounds for all 4 weeks. Neither kava nor valerian relieved anxiety or insomnia more than placebo. This trial demonstrates the feasibility of conducting randomized, blinded trials entirely via the Internet.

Adult↗
PubMed2006

The effects of oral pancreatic enzymes (Creon 10 capsule) on steatorrhea: a multicenter, placebo-controlled, parallel group trial in subjects with chronic pancreatitis.

OBJECTIVES: Creon 10 Minimicrospheres is an enteric-coated, delayed-release pancrelipase preparation designed to deliver active pancreatic enzymes to the small intestine. The primary objective of this study was to compare the effect of Creon 10 with placebo in the control of steatorrhea in chronic pancreatitis patients. Secondary objectives included evaluation of stool parameters and global improvement of symptoms scales. METHODS: The study was a randomized, double-blind, placebo-controlled, 2-week trial. After a placebo run-in ("washout") phase, the effect on coefficient of fat absorption (%), daily fat excretion before and after treatment, and stool frequency and consistency were assessed. RESULTS: In Creon 10-treated subjects, the change in mean coefficient of fat absorption (%) from run-in to double-blind phase was significantly higher compared with placebo-treated subjects (+36.7 vs. +12.1, P = 0.0185). Stool consistency improved significantly more with Creon 10 than with placebo (P = 0.0102) resulting in more subjects with formed stool; stool frequency decreased significantly more with Creon 10 than with placebo (P = 0.0015) from 10.8 during placebo run-in to 5.2 stools per day during double-blind treatment; and daily mean fat excretion in stool decreased significantly more (-56.5 vs. -11.4 g/d, P = 0.0181) in Creon 10-treated subjects compared with placebo-treated subjects. Global disease symptom scores showed greater improvement for both physicians and subjects in the Creon 10 group relative to those receiving placebo. Between treatment difference reached statistical significance for Creon 10 (P = 0.0435) for physician score and showed a trend (P = 0.0634) favoring Creon for subject score. CONCLUSIONS: This randomized, placebo-controlled trial found that Creon 10 treatment controlled steatorrhea, as reflected in reduced fat excretion, decreased stool frequency and improved stool consistency. Creon 10 treatment was safe and well tolerated.

Administration, Oral↗
PubMedDate not supplied

The association between psychopathology and placebo analgesia in patients with discogenic low back pain.

BACKGROUND: Chronic low back pain patients have a high rate of psychopathology, comprised mainly of depression, anxiety, and high levels of neuroticism. We previously found that psychopathology is associated with increased placebo analgesia in this patient group. OBJECTIVE: To better understand this finding in the context of other known predictors of placebo response (such as expectations for relief), we performed a detailed analysis of expectations and other possible covariates. DESIGN: We conducted a double-blind, placebo-controlled, randomized, crossover-designed trial of intravenous morphine vs. placebo in 60 subjects with chronic low back pain and discogenic abnormalities. Patients were stratified into three groups of psychiatric symptom severity (Low, Moderate, and High), based on composite scores on depression, anxiety for pain, and neuroticism scales. Subjects were given intravenous morphine and placebo in random order on separate visits, and completed serial pain ratings over 3 h at each session. RESULTS: With 20 subjects per group, there were small, but significant differences between groups in baseline pain ratings. No differences were found between groups in age, gender, and radicular pain. Patients with low psychological symptomatology reported 7.7% total pain relief with placebo compared with 23.4% in the Moderate group and 23.5% in the High group (P < 0.05). Expectations were not significantly different between groups, but in the High group expectation levels predicted placebo analgesia (P < 0.001). Neuropathic pain quality was also a predictor (P < 0.05). CONCLUSIONS: This study indicates that high and moderate levels of psychopathology are associated with heightened placebo analgesia in chronic low back pain patients. Expectations were only an influence in the high psychopathology group, and neuropathic pain affects placebo responses. These findings have implications for future research characterizing placebo responders.

Adult↗
PubMed2004

The role of endogenous opioids in the placebo effect in post-traumatic stress disorder.

The concept of the placebo effect has received a considerable attention over the past several decades. The placebo effect has been observed in different psychiatric disorders, including post-traumatic stress disorder (PTSD), a chronic and severe disorder precipitated by exposure to a psychologically distressing event. The placebo response rates in patients with PTSD range from 19% to 62%. A considerable number of research publications suggest that endogenous opioids are involved in the mechanisms of the placebo effect. Endogenous opioid peptides play an important role in stress response and in the pathophysiology of PTSD. Therefore, endogenous opioids may be involved in the neurobiology of the placebo effect in PTSD. Possibly, the endogenous opioid system mediates the effect of placebo on all 3 PTSD symptom clusters (re-experiencing symptoms, avoidance and numbing, and physiologic arousal). The placebo effect-related activation of the endogenous opioid system may result in an improvement in intrusive symptomatology and symptoms of increased arousal because the administration of exogenous opioids improve these symptoms. The placebo effect-related activation of the endogenous opioid system may have a mood-enhancing effect, and, consequently, diminish avoidance and numbing. Multiple neurotransmitter and neuroendocrine pathways may be involved in the mechanisms of the placebo effect in PTSD. Further studies of the neurobiology of the placebo effect on patients with PTSD and other psychiatric disorders may produce interesting and important results.

Dynorphins↗
PubMed2005

Mechanisms of the placebo effect and of conditioning.

A placebo is a sham treatment, such as a pill, liquid, or injection without biological activity, used in pharmacology to control for the activity of a drug. However, 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, which sees the patient's expectation as the primary cause of the placebo effect. The mechanisms involved in these processes are beginning to be understood through new techniques of investigation in neuroscience. Dopamine and the endorphins have been clearly shown to be mediators of placebo effects. Brain imaging has demonstrated that placebos can mimic the effect of the active drugs and activate the same brain areas. This is the case for placebo-dopamine in Parkinson's disease, for placebo-analgesics or antidepressants, and for placebo-caffeine in the healthy subject. It remains to be understood how conditioning and expectation are able to activate memory loops in the brain that reproduce the expected biological responses.

Animals↗
PubMed2000

Lubeluzole in acute ischemic stroke treatment: A double-blind study with an 8-hour inclusion window comparing a 10-mg daily dose of lubeluzole with placebo.

BACKGROUND AND PURPOSE: This trial was a double-blind, placebo-controlled, phase III trial with an 8-hour inclusion window to assess the efficacy and safety of an intravenous loading dose of 7.5 mg followed by a daily intravenous dose of 10 mg lubeluzole for 5 days in acute ischemic stroke patients. METHODS: A total of 1786 patients were randomized: 901 to lubeluzole and 885 to placebo. Overall, 212 patients (23.5%) from the lubeluzole group and 213 (24.1%) from the placebo group discontinued the trial prematurely. In the lubeluzole group 201 patients (22.3%) discontinued because of adverse events compared with 193 patients (21.8%) in the placebo group. RESULTS: The primary population for the efficacy analysis comprised the core stroke patients (exclusion of older patients aged >75 years with severe stroke) in the 0- to 6-hour inclusion time window. The primary efficacy parameter was a 3-category functional status (Barthel Index 70 to 100/0 to 70/vegetative, dead) at week 12. In the lubeluzole group 207 patients (47.8%) were classified as mildly dependent/independent at week 12, 131 (30.3%) were moderately/severely dependent, and 95 (21.9%) were vegetative/dead. In the placebo group these numbers were 221 (54.4%), 112 (27.6%), and 73 (18.0%), respectively. Logistic regression analysis showed no statistically significant difference between the treatment groups (P:=0.162). Additionally, for none of the secondary efficacy parameters (mortality at week 12, modified Rankin score, total Barthel score) was a statistically significant difference between the lubeluzole and placebo groups obtained. There were no statistically significant differences between the 2 treatments for all treated patients, patients included within the 6- to 8-hour window, and patients with severe strokes aged >75 years. Overall, of all treated patients, 401 (22.5%) died: 203 (22.5%) in the lubeluzole group and 198 (22.4%) with placebo. Of all subjects treated, 853 (95%) on lubeluzole and 826 (93%) on placebo reported an adverse event during their treatment period or within the next 2 days after discontinuation of treatment. The most frequently observed adverse events were fever (25.9% lubeluzole; 23.4% placebo), constipation (20.2%; 19.7%), and headache (17.6%; 21.2%). Imbalances were found for atrial fibrillation (1.8% lubeluzole; 1.1% placebo) and QT prolongation (0.9%; 0.2%). CONCLUSIONS: This study failed to show an efficacy of lubeluzole in the treatment of acute stroke. On the other hand, lubeluzole treatment by the current dosage schedule was not associated with a significant safety problem.

Acute Disease↗
PubMed2003

The Declaration of Helsinki and clinical trials: a focus on placebo-controlled trials in schizophrenia.

OBJECTIVE: The authors' goal was to consider ethical approaches to placebo-controlled clinical trials in the light of the evolving Declaration of Helsinki, with special attention to applications to research on schizophrenia. METHOD: They review the Helsinki position on placebos, including the 2002 Clarification, exploring the potential negative effects of banning placebos in studies involving conditions for which at least partially effective treatments exist. The Clarification is examined as an approach to this issue that, in contrast to earlier formulations, better acknowledges the complexity of clinical research and the need for protocol-specific determinations. Placebo controls in schizophrenia studies are used to illustrate issues relevant to all clinical research on therapeutic interventions. RESULTS: The Helsinki Clarification provides a basis for operationalizing criteria for review of placebo use in clinical trials. Six criteria are proposed for judging the ethical acceptability of placebo controls, including the likelihood that the intervention being tested will have clinically significant advantages over existing treatments, the presence of compelling reasons for placebo use, subject selection that minimizes the possibility of serious adverse consequences, and a risk-versus-benefit analysis that favors the advantages from placebo use over the risks to subjects. CONCLUSIONS: The Helsinki Clarification constitutes an important advance in international approaches to placebo use, requiring protocol-by-protocol judgments on complex issues of clinical research ethics. When operationalized, it provides review boards with a useful methodology for reaching determinations on the appropriateness of placebo controls in particular studies.

Controlled Clinical Trials as Topic↗
PubMed2003

An 8-week multicenter, parallel-group, double-blind, placebo-controlled study of sertraline in elderly outpatients with major depression.

OBJECTIVE: There have been few placebo-controlled trials of selective serotonin reuptake inhibitors for depressed elderly patients. This placebo-controlled study of sertraline was designed to confirm the results of non-placebo-controlled trials. METHOD: The subjects were outpatients age 60 years or older who had a DSM-IV diagnosis of major depressive disorder and a total score on the 17-item Hamilton Depression Rating Scale of 18 or higher. The patients were randomly assigned to 8 weeks of double-blind treatment with placebo or a flexible daily dose of 50 or 100 mg of sertraline. The primary outcome variables were the Hamilton scale and Clinical Global Impression (CGI) scales for severity and improvement. RESULTS: A total of 371 patients assigned to sertraline and 376 assigned to placebo took at least one dose. At endpoint, the patients receiving sertraline evidenced significantly greater improvements than those receiving placebo on the Hamilton depression scale and CGI severity and improvement scales. The mean changes from baseline to endpoint in Hamilton score were -7.4 points (SD=6.3) for sertraline and -6.6 points (SD=6.4) for placebo. The rate of CGI-defined response at endpoint was significantly higher for sertraline (45%) than for placebo (35%), and the time to sustained response was significantly shorter for sertraline (median, 57 versus 61 days). There were few discontinuations due to treatment-related adverse events, 8% for sertraline and 2% for placebo. CONCLUSIONS: Sertraline was effective and well tolerated by older adults with major depression, although the drug-placebo difference was not large in this 8-week trial.

Age Factors↗
PubMed2005

Suicide risk in placebo-controlled trials of treatment for acute manic episode and prevention of manic-depressive episode.

OBJECTIVE: The authors' goal was to investigate whether there is a greater suicide risk in the placebo arms of placebo-controlled studies of active medication for the treatment of acute manic episode and the prevention of manic/depressive episode. If so, this would be a strong ethical argument against the conduct of such studies. METHOD: All placebo-controlled, double-blind, randomized trials of medication for the treatment of acute manic episode and the prevention of manic/depressive episode that were part of a registration dossier submitted to the regulatory authority of the Netherlands, the Medicines Evaluation Board, between 1997 and 2003, were reviewed for occurrence of suicide and attempted suicide. RESULTS: In 11 placebo-controlled studies of the treatment of acute manic episode, including 1,506 patients (117 person-years) in the combined active compound group and 1,005 patients (71 person-years) in the combined placebo group, no suicides and no suicide attempts occurred. In four placebo-controlled studies of the prevention of manic/depressive episode, including 943 patients (406 person-years) in the combined active compound group and 418 patients (136 person-years) in the combined placebo group, two suicides (493/100,000 person-years of exposure) and eight suicide attempts (1,969/100,000 person-years of exposure) occurred in the combined active compound group, but no suicides and two suicide attempts (1,467/100,000 person-years of exposure) occurred in the combined placebo group. CONCLUSIONS: Concern about greater risk of suicide or attempted suicide in the placebo group should not be an argument against the conduct of placebo-controlled trials for these indications, provided that appropriate precautions are taken.

Acute Disease↗
PubMed2001

The placebo response in social phobia.

The placebo response forms a growing problem in randomized, placebo-controlled clinical trials in psychiatry. Research into the placebo response is on the increase, but remains very limited in relation to social phobia. Together with the dropout rate, the placebo effect is an important factor limiting the discriminative properties of any study. In this study, we reviewed 15 placebo-controlled studies in social phobia, focussing on patients and study characteristics. In social phobia, the placebo effect has turned out to be moderately large and has shown no increase over the past decade. Placebo response was highest in large, multicentred trials and was independent of study duration. No validation for a placebo run-in was found. Taking into account both response to placebo and active drug, as well as dropout rate, the most discriminative results are probably to be expected in a sample of patients who are moderately to severely impaired. More research in the field of the placebo response is needed.

Double-Blind Method↗
PubMed2005

Placebo response in clinical trials of depression and its implications for research on chronic neuropathic pain.

This article reviews studies of the placebo response in antidepressant clinical trials, describes methods that have been attempted to decrease it, and discusses implications of the placebo response in depression for research on treatments for neuropathic pain. Literature reviews and research studies examining the placebo response in clinical trials of treatments for depression were reviewed. Existing data suggest that the placebo response in antidepressant clinical trials is substantial and that a high placebo response in a clinical trial is associated with a reduced likelihood of demonstrating the statistical superiority of antidepressant treatment vs. placebo. Attempts to decrease the placebo response in antidepressant clinical trials have generally not been effective. In addition, there is little evidence that decreasing the placebo response rate makes it more likely that superiority of active vs. placebo treatment will be demonstrated. Analyses of neuropathic pain clinical trial databases should be conducted to examine factors associated with trial outcomes. Aspects of neuropathic pain clinical trials that require further consideration or investigation include the following: (a) exclusion of patients with mild pain severity; (b) exclusion of patients with short episode duration; (c) maximizing reliability, validity, and responsiveness of outcome measures; (d) minimizing extraneous contact with investigative staff and other sources of nonspecific therapeutic effects; (e) trial duration; (f) minimizing the number of treatment groups; (g) flexible vs. fixed dose designs; (h) strategies for identifying patients and accelerating enrollment; (i) identification of run-in periods that reduce the placebo response rate; and (j) registration of clinical trials and publication of negative studies.

Antidepressive Agents↗
PubMed2005

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.

Analgesia↗
PubMed2005

Is there a placebo problem in antidepressant trials?

In psychiatry, particularly in antidepressant clinical studies, placebo-controlled trials often yield results that are very difficult to interpret because of robust placebo responses. Meta-analyses of trials in major depressive disorder (MDD) suggest that drug-placebo differences in response rates range from 11% to 18%. However, in trials of marketed antidepressants present in the FDA databases, antidepressant drugs were superior to placebo in only 45 out of 93 RCTs (48%), and the placebo response overall appears to have increased over time. This gradual increase in placebo response rates may lead to delays in bringing new antidepressant treatments to the market, increased costs of antidepressant drug development and, in some cases, decisions to stop the development of certain compounds, or FDA decisions to not approve new treatments. A number of possible contributing factors to this significant placebo response in MDD have been identified, but further studies are needed. Many of the remedies used by researchers to minimize the placebo response, such as lead-in periods or shortening the duration of study visits, have failed to show consistent benefits. From our analysis of published studies, it appears that expectations about the speed of response may be shaped by the duration of the trial and that most of the placebo response occurs in the first half of the trial, regardless of its duration. These observations have led us to develop a novel approach to the placebo response problem called the Sequential Parallel Comparison Design.

Antidepressive Agents↗
PubMed1996

Placebo effects in the pharmacological treatment of uncomplicated benign prostatic hyperplasia. The ALFECH Study Group.

In order to establish accurately the exact effect of any drug therapy for symptomatic benign prostatic hyperplasia (BPH) it is important to define the effect of placebo treatment. This effect was assessed by throughly analyzing the placebo arm, which included 101 patients, from a randomized, double-blind, placebo-controlled trial of the selective alpha-blocker alfuzosin and comparing the data with those of a variety of independent studies which followed a placebo group of patients with clinical BPH. Following 16 weeks of placebo treatment a decrease of 24% (p < 0.05) in Madsen-Iversen score and an increase of 14% (p < 0.05) in peak flow rate was demonstrated. The percentages of patients who reported worsening, improvement or no change in symptoms were 9.2%, 73.6% and 17.2% respectively. The maximal effect of placebo, approximately 40% reduction in symptom scores, is likely to be achieved within the first four to six months. After this, the placebo effect stabilizes and gradually wears off but is still present following 12 months of treatment. The duration of the placebo effect and the time until it has totally worn off, if ever, remains to be studied in long-term, placebo-controlled trials, including an untreated cohort. The present study emphasizes the importance of properly designed, double-blind, placebo-controlled studies in evaluating any pharmacological intervention in clinical BPH.

Adrenergic alpha-Antagonists↗