High Placebo Effect Research Articles

Psychological Stress in Chronic Intestinal Diseases

Psychological stress induces alterations in the function of the hypothalamic-pituitary-adrenal axis via corticotorphin releasing factor and alterations in the enteric nervous system via actions of the autonomic nervous system. Mucosal mast cells and adrenal glands release several inflammatory cytokines and cortisol, causing increased intestinal permeability. Increased intestinal permeability as well as increased inflammatory cytokines and hormones cause changes in bacterial-mucosal interactions, leading to the aggravation of disease activity and gastrointestinal symptoms in inflammatory bowel syndrome (IBD) and irritable bowel syndrome (IBS). Several studies have demonstrated that stress has an important roles in the pathogenesis of IBD and IBS. Personal traits, health beliefs and personal stress-coping mechanisms can also have adverse effects on the disease course of IBD and IBS. Stress reduction therapies have been adapted for treatment of IBD and IBS. Antidepressants and psychological therapies such as cognitive-behavior therapy, hypnotherapy, and multi-component psychological therapy have been used for control of disease activity and symptoms in IBD and IBS patients. The efficacy of such treatments is controversial, because there has not been an adequate standardization in treatment protocol, and studies suffer from the difficulties involved in selection of appropriate control groups, questions related to a high placebo effect, as well as differences in interpretation. Well-designed prospective controlled studies evaluating the role of stress in the pathogenesis of IBD and IBS and the role of stress reduction therapies are warranted for improvement of clinical treatments and outcomes.

Adverse events appear to unblind clinical trials in irritable bowel syndrome

Clinical trial design is challenging in irritable bowel syndrome (IBS) due in part to a high placebo effect. We postulated that the mere presence of an adverse event (AE) may unmask patients in clinical trials who are assigned to the active agent, and this may lead to higher reported efficacy. We evaluated therapies receiving at least a Grade 1B from the American College of Gastroenterology Task Force for IBS or which passed recent phase III clinical trials. Therapies with AE data derived from less than 50 patients in each study arm were excluded. Statistically significant excess AE were identified, risk difference was calculated for each AE, and incidence of AE in the treatment arm was reported. We examined the relationship of attributable drug benefit, defined as the reciprocal of number-needed-to-treat found in literature, with various measures of AE incidence. Attributable drug benefit correlated significantly with average AE risk difference, calculated as treatment arm AE incidence minus placebo arm AE incidence (R(2) = 0.70, p = 0.039), and also with highest treatment arm AE incidence (R(2) = 0.70, p = 0.038) for each therapy. There were also trends toward correlation with average treatment arm AE incidence (R(2) = 0.54, p = 0.096) and highest AE risk difference (R(2) = 0.63, p = 0.059) for each therapy. Our study suggests that higher AE incidence on active therapy is associated with more beneficial patient-reported outcomes in IBS clinical trials. This raises the issue of spontaneous unblinding.

Modelling and simulation of placebo effect: application to drug development in schizophrenia

High and variable placebo effect (PE) within and among clinical trials can substantially affect conclusions about the efficacy of new drugs in the treatment of schizophrenia and other neuropsychiatric disorders. In recent years, it has become increasingly difficult to prove drug efficacy against placebo, and one of the reasons is that the placebo response has increased over recent years. The increased placebo response over the years is partly explained by unidentified parallel interventions, patient factors, issues with trial designs, and regional variability or demographic differences. In addition, a nocebo effect, which is undesirable effects a subject manifests after receiving placebo, e.g. extrapyramidal side effects, in placebo arms of antipsychotic trials could also influence the PE and clinical trial outcomes. Placebo effects (PEs) are a natural phenomenon and cannot be avoided completely in clinical trials. However, accounting for the PE via mixed effects modelling approaches could reduce bias in quantifying the overall effect size of the drug treatment. This review article focuses on the PE and its impact on schizophrenia clinical trial outcomes. The authors briefly describe the factors that lead to high and variable PE. Next, pharmacometric approaches to account for the PE and dropouts in schizophrenia clinical trials are described. Finally, some points are provided that could be considered while designing and optimizing antipsychotic trials via simulation approaches.

3034 – Efficacy of antidepressant and psychotherapeutic treatments in child and adult depression and anxiety

Depressive and anxiety disorders are prevalent psychiatric disorders that often start early in life. Heterotypic association between depression and anxiety has been well documented, with anxiety typically preceding depression in childhood and adolescence, while a more complex pattern of co-occurrence has been described for adult-onset illness. Even when starting early in life, depression and anxiety disorders are associated with poor outcomes, including not only psychiatric, social and vocational outcomes, but also development of physical problems. Although remission rates are high, in most cases episodes tend to recur, with increasing severity with every recurrence. Identification and treatment of these conditions, therefore, is of outmost importance regardless their age of onset. However, therapeutic approaches must take into account the effect of development in their clinical presentation, the differential efficacy of the therapeutic approaches, and the adverse effects profile. Current treatment algorithms for depressive and anxiety disorders include psychotherapeutic and psychopharmachological approaches and their combination. Although up until recently most treatment evidence came from adult studies, recent developments have increased knowledge on efficacy of interventions for younger populations. Treatment effects in children and adolescents are lower than in adults, partially due to the high placebo effect in youth. This presentation will provide an overview of the current approach to the treatment of depression and anxiety. Specificity of treatment at early ages will be stressed out. New promising treatments and their potential utility will be also discussed.

Randomized, double-blind, placebo-controlled, phase II trial of gabapentin enacarbil for migraine prophylaxis

The objective of this article is to evaluate the efficacy and safety of gabapentin enacarbil (GEn) for migraine prophylaxis. In this randomized, double-blind, parallel-group study, patients with International Headache Society-defined migraine who met criteria suggesting the need for prophylactic therapy were randomized 2:1:2:2:1 to one of the following five groups, designated according to target daily dose of study medication during the 20-week treatment period: placebo, GEn 1200 mg, GEn 1800 mg, GEn 2400 mg, or GEn 3000 mg. The intent-to-treat population included 523 patients (n = 128 placebo, n = 66 GEn 1200 mg, n = 134 GEn 1800 mg, n = 133 GEn 2400 mg, n = 62 GEn 3000 mg). No statistically significant difference between active treatment (the average of 1800 mg and 2400 mg treatment groups) and placebo was found for change from baseline in the number of migraine headache days during the last four weeks of treatment prior to taper (the primary endpoint). Results of analyses of the primary endpoint using the per protocol population, analyses using imputation methods different from those of the primary analysis, and nonparametric analyses were consistent with the primary analysis in showing no difference between active treatment and placebo. The pattern of results was similar for the secondary efficacy endpoints. Pharmacokinetic data demonstrate that patients had adequate estimated exposure to GEn. The adverse event profile of GEn was consistent with that in previous studies. GEn did not significantly differ from placebo for migraine headache prophylaxis. A high placebo effect should be considered when interpreting these results.

Modelling and Simulation of the Positive and Negative Syndrome Scale (PANSS) Time Course and Dropout Hazard in Placebo Arms of Schizophrenia Clinical Trials

The likelihood of detecting a therapeutic signal of an effective drug for schizophrenia is impeded by a high placebo effect and by high dropout of patients. Several unsuccessful trials of schizophrenia, at least partly due to highly variable placebo effects, have indicated the necessity for a robust methodology to evaluate such a placebo effect and reasons for dropout. Hence, the objectives of this analysis were to (i) develop a longitudinal placebo model that accounts for dropouts and predictors of the placebo effect, using the Positive and Negative Syndrome Scale (PANSS) score; (ii) compare the performance of empirical and semi-mechanistic placebo models; and (iii) compare different time-to-event (TTE) dropout modelling approaches used to account for dropouts. The PANSS scores from 1436 individual patients were used to develop and validate a placebo model. This pooled dataset included 16 trials (conducted between 1989 and 2009), with different study durations, in both acute and chronic schizophrenic patients. A nonlinear mixed-effects modelling approach was employed, using NONMEM VII software. Among the different tested placebo models, the Weibull model and the indirect response model adequately described the PANSS data. Covariate analysis showed that the disease condition, study duration, study year, geographic region where the trial was conducted, and route of administration were important predictors for the placebo effect. All three parametric TTE dropout models, namely the exponential, Weibull and Gompertz models, described the probability of patients dropping out from a clinical trial equally well. The study duration and trial phase were found to be predictors for high dropout rates. Results of joint modelling of the placebo effect and dropouts indicated that the probability of patients dropping out is associated with an observed high PANSS score. The indirect response model was found to be a slightly better model than the Weibull placebo model to describe the time course of the PANSS score. Our modelling approach was shown to adequately simulate the longitudinal PANSS data and the dropout trends after placebo treatment. Data analyses suggest that the Weibull and indirect response models are more robust than other placebo models to describe the nonlinear trends in the PANSS score. The developed placebo models, accounting for dropouts and predictors of the placebo effect, could be a useful tool in the evaluation of new trial designs and for better quantification of antipsychotic drug effects.

Ensocopic-endoluminal therapies. A critical appraisal

Due to its large prevalence, gastro-oesophageal reflux disease is an ideal target for companies developing medical devices designed to cure reflux. Indeed, because medications leave part of the patients unsatisfied, there is a potential place for alternative therapies, capable of restoring an efficacious anti-reflux barrier, but without the drawbacks of surgery. For more than a decade, several novel endoluminal therapies were developed, clinically evaluated, put on the market and, for many of them, withdrawn due to economic considerations, lack of efficacy or complications. These therapies were designed to act on the gastro-oesophageal junction and reinforce mechanically the anti-reflux barrier by three different ways: suturing, radiofrequency energy application, or implantation of foreign materials. Most of the published data come from open uncontrolled studies with short-term enthusiastic results. There are a few randomized control trials assessing the true efficacy of these modalities, showing often less impressive results than the open studies did, due to a high placebo effect in mild gastro-oesophageal reflux disease. Although endoscopic treatment of gastro-oesophageal disease is still an interesting topic of investigation, one can draw some lessons from the recent experiences and foresee which place these techniques could find in the management of patients suffering from reflux.

Pilot, multicenter, double-blind, randomized placebo-controlled bilateral comparative study of a combination of calcipotriene and nicotinamide for the treatment of psoriasis

Calcipotriene has limited efficacy in treating psoriasis. By inhibiting proinflammatory cytokines such as interleukin-12, interleukin-23, and tumor necrosis factor-alfa, nicotinamide may enhance the efficacy of calcipotriene therapy when used in combination. We sought to determine if the combination of nicotinamide with calcipotriene is more effective than either component alone. In this randomized, double-blinded, multicenter 7-arm bilateral comparison-controlled trial, patients were randomized to two of 7 treatments--placebo, calcipotriene 0.005% alone, nicotinamide 1.4% alone, calcipotriene plus nicotinamide 0.05%, calcipotriene plus nicotinamide 0.1%, calcipotriene plus nicotinamide 0.7%, or calcipotriene plus nicotinamide 1.4%--each administered to lesions on one side of the body or to one of two lesions at least 5 cm apart, for 12 weeks. Efficacy was measured using a clear to almost clear outcome. In all, 50.0% of patients in the calcipotriene and nicotinamide 1.4% combination group achieved a clear to almost clear outcome at week 12, compared with only 18.8% of patients treated with placebo (P = .002), 25% of patients treated with nicotinamide 1.4% alone (P = .02), and 31.5% of patients treated with calcipotriene alone (P = .096). A dose-response trend existed for increasing concentrations of nicotinamide, but it was not significant. The relatively small patient numbers, relatively high placebo effect, and maximum in-life portion of only 12 weeks of dosing are weaknesses of the study. This study provides evidence that using the combination nicotinamide and calcipotriene may provide additional benefit in the topical treatment for patients with psoriasis and may be an adequate steroid-sparing substitute treatment.

Potential benefits of probiotics – main findings of an in-depth review

Media reports on probiotics have been conflicting which has led to increased confusion among the general population and also among health professionals. To disentangle myths and reality, the British Nutrition Foundation has carried out a review on probiotics and health. There is good evidence that probiotics are effective in preventing antibiotic-associated diarrhoea and, although only few studies have been carried out so far, probiotic microorganisms also seem to have the potential to prevent the potentially fatal Clostridium difficile-associated diarrhoea. A limited number of studies that are available on the effectiveness of probiotics on constipation have shown conflicting results, but promising results have been found for certain strains. Irritable bowel syndrome symptoms have been found to be reduced by consuming probiotic strains, although a high placebo effect has been observed in some of the studies. The field of probiotics is relatively new and more studies will be needed to allow firm conclusions on the effectiveness of probiotic microorganisms for certain health issues.

Management of laryngopharyngeal reflux: an unmet medical need

Laryngopharyngeal reflux (LPR) is defined by the association of laryngeal symptoms with laryngeal inflammation at laryngoscopy. However, these symptoms are difficult to characterize and the laryngoscopic signs lack specificity. Moreover, to date, the diagnosis of LPR can rely neither on esophageal investigations (endoscopy, pH/impedance monitoring) nor on response to high dose proton pump inhibitors because of a high placebo effect. Therefore, there is a need for the development of new tools which may help to better identify the subgroup of patients with laryngeal symptoms related to supra-esophageal reflux.

Neuronal correlates in the modulation of placebo analgesia in experimentally-induced esophageal pain: A 3T-fMRI study

Visceral pain/discomfort is the cardinal complaints and treatment targets for functional gastrointestinal disorders (FGID). However, effective treatment for such pain is limited and often associated with high placebo effects. The mechanisms of placebo effects in visceral pain are unclear. We used functional neuroimaging to study the central representations of the placebo effect and its anticipation during esophageal pain in healthy adults. Fourteen subjects were enrolled. Pain extent, psychophysical inventories [Pain Catastrophizing Scale (PAS), visual analogue scale (VAS) and short-form McGill questionnaire], and brain activity upon placebo intervention and upon anticipation were assessed in response to esophageal balloon distension. Large reductions of pain extent, VAS rating, short-form McGill questionnaire scores, and brain activity in the visceral pain matrix [thalamus, somatosensory cortices, insula, prefrontal cortex (PFC), anterior cingulate cortex] were observed upon placebo treatment. The aforementioned brain areas and the bilateral amygdala were significantly correlated with decreased pain extent and VAS in response to placebo. The ventral lateral PFC (VLPFC) was associated with increased activity during anticipation of visceral pain. PAS cannot predict the placebo effect in visceral pain. In conclusion, pronounced placebo analgesia was coupled with prominent changes of brain activity in visceral pain matrix, which are thus likely involved in high placebo efficacy during the treatment of visceral pain in FGID. VLPFC activation during the anticipation of placebo analgesia suggests top-down control in the modulation of pain experience.

Probiotics and health: a review of the evidence

SummaryProbiotics are live microorganisms – mainly bacteria – which when administered in adequate amounts confer a health benefit on the host. There is rising interest in this area, but reports in the media are often conflicting. The aim of this review is to consider the current evidence on the effects of probiotics on health, focusing on gut‐related health issues and the immune system, with the objective to provide a clearer picture of whether and how probiotics can be beneficial for health. The outcomes of this review are based on more than 100 original studies, meta‐analyses and systematic reviews. A variety of different strains have been used in studies on probiotics, and it is important to remember that the effectiveness of probiotics is strain‐specific, which means that each single probiotic strain has to be tested to assess its potential health benefits.Overall, despite the diversity of strains used in the studies included in this review, there is evidence that probiotics have the potential to be beneficial for our health. Studies in patients with inflammatory bowel disease show probiotic strains to be able to decrease the recurrence of ulcerative colitis and occurrence and recurrence of pouchitis, however, current evidence suggests that probiotics are ineffective in treating patients with Crohn's disease. Patients with irritable bowel syndrome show a reduction in symptoms when treated with selected probiotic strains, but high placebo effects have been reported as well. The evidence of the efficacy of probiotics in patients suffering from constipation is limited, but the evidence seems promising for some strains to bring relief to patients suffering from constipation.There is good evidence that a number of probiotic strains are effective in preventing antibiotic‐associated diarrhoea. The most commonly studied strains are Lactobacillus rhamnosus GG (LGG) and Saccharomyces boulardii, but other strains and mixtures of strains seem to be effective as well. There is also promising evidence of a preventive effect of probiotics in Clostridium difficile‐associated diarrhoea, although some studies have been too small to obtain statistically significant findings. The effect of probiotics in acute diarrhoea, particularly in children, is well studied. Selected probiotic strains seem to be effective in reducing the duration of acute diarrhoea. LGG and S. boulardii are again the most commonly used strains and a number of studies have shown them to be effective, although one meta‐analysis showed that the effect of LGG was only significant in children in Western countries, not in children in developing countries, which may be due to different causes of diarrhoea in these regions. Studies investigating the preventive effect of probiotics in the context of common cold and flu infections show that the studied strains failed to lower the incidence of episodes but that they have the potential to decrease the duration of episodes, which suggests that the immune system may be more efficient in fighting off common cold and flu infections after consuming these strains. The evidence so far does not suggest that probiotics are effective in preventing or treating allergies or in treating eczema. However, some probiotic strains seem to lower the risk of developing eczema if taken by pregnant women and their infants in early life.

This Month in Gastroenterology

This Month in Gastroenterology

A meta-analysis of the placebo response in antimuscarinic drug trials for overactive bladder

BackgroundThe purpose of this analysis was to characterize the placebo response in antimuscarinic drug trials for OAB, based on changes in commonly-used efficacy endpoints.MethodsPlacebo arm data for incontinence episodes, micturitions, voided volume and study characteristics were extracted from randomized placebo controlled antimuscarinic drug trials in OAB, from studies identified in a prior meta-analysis, and from a systematic review of more recently published studies. Relationships between variables were examined using linear regression, and changes in endpoints were analyzed by a meta-analysis approach. The effect of placebo arm size and magnitude of placebo response on probability of successful study outcome was analyzed using an ANOVA model.ResultsChanges in the placebo arms for all 3 endpoints were substantial and statistically significant, and highly heterogeneous. There were significant associations between baseline and change scores for some but not all of the endpoints. More recent studies tended to have more subjects than earlier studies, and there were positive associations between probability of achieving statistically significant results and size of the placebo arm. The magnitude of changes in placebo arms did not appear to influence the likelihood of the study to be statistically significant.ConclusionThis analysis confirms earlier observation that the placebo response in OAB trials is substantial and highly heterogeneous. There are multiple potential reasons for this; however, these could not be explored in this analysis of study-level data. Two approaches may be used in clinical trials to manage high placebo effect: recruitment of 1) greater numbers of patients and/or 2) more severely affected patients; however, only the former approach is associated with increased probability of successful study outcome.

Efficacy of Botulinum Toxin Type A for the Prophylaxis of Episodic Migraine Headaches: A Meta‐analysis of Randomized, Double‐Blind, Placebo‐Controlled Trials

To assess the efficacy of botulinum toxin type A in lowering the frequency of migraine headaches in patients with episodic migraines. Meta-analysis of eight randomized, double-blind, placebo-controlled trials. A total of 1601 patients with a history of episodic migraine headaches classified as those experiencing headaches fewer than 15 times/month over a 3-month period. PubMed, Google Scholar, and the Cochrane Library were searched from inception to October 2007 in order to locate randomized, double-blind, placebo-controlled trials that compared the efficacy of pericranial botulinum toxin A injections with placebo in the prevention of migraines in patients with a history of episodic migraine headaches. The primary outcome of interest was change from baseline to end point in migraine frequency (number of migraines/month). A random effects model was used to combine study results, and the standardized mean difference (Cohen's d) in migraine frequency between the placebo and botulinum toxin A groups was reported. Effect sizes (d) less than 0.2 were considered small. Quality assessment was performed by using the Downs and Black scale. Eight randomized, double-blind, placebo-controlled clinical trials (1601 patients) presented a quantitative assessment of the efficacy of botulinum toxin A versus placebo. The overall treatment effect size of botulinum toxin A over placebo for 30, 60, and 90 days after injection was d -0.06 (95% confidence interval [CI] - 0.14-0.03, z=1.33, p=0.18), d -0.05 (95% CI -0.14-0.03, z=1.22, p=0.22), and d -0.05 (95% CI -0.13-0.04, z=1.07, p=0.28), respectively. Even after controlling for a high placebo effect, and after dose stratification, no significant effect of botulinum toxin A in reducing migraine frequency/month was seen over placebo. Botulinum toxin A for the prophylactic treatment of episodic migraine headaches was not significantly different from placebo, both from a clinical and statistical perspective.

Erratum

Torgovnik and colleagues' letter offers us the opportunity to clarify some of our results. Torgovnik and colleagues state that the number of patients included in our study1 was small, and that some recovered with placebo, whereas others did not respond to botulinum toxin type A (BTX-A). We would counter that the results of our controlled and blinded study were straightforward on most outcomes. We also acknowledge that large samples are generally needed to achieve significance in pharmacological studies of neuropathic pain.2 The recovery observed in a few placebo-treated patients is in keeping with generally high placebo effects in neuropathic pain.3 The fact that BTX-A was poorly effective in some patients is consistent with meta-analyses showing that the proportion of responders to antineuropathic drugs generally does not exceed 30%.2 Interestingly, the effects of BTX-A were inversely correlated to the severity of thermal deficits (eg, nonresponders had more severe nociceptive fiber impairment than those who responded well to treatment),1 which constitutes a first step toward identifying responder profiles to BTX-A. Torgovnik and colleagues state that the evidence for efficacy of BTX-A is not infallible in neuropathic pain and migraine. Disparate findings were, indeed, reported with BTX-A in migraine in several class I trials4; however, our study is the first class I trial showing efficacy in painful focal neuropathies. The results obtained with BTX-A in migraine, the mechanism of which bears little similarity to that of neuropathic pain, cannot preclude efficacy in neuropathic pain. More generally, Torgovnik and colleagues appear to address the relevance of evidence-based medicine; however, well-conducted, randomized, placebo-controlled trials are crucially needed in neuropathic pain and have notably contributed to the disregard of various ineffective treatments, such as benzodiazepines and sympatholytics.2 Although we acknowledge that further trials are necessary to expand indications for botulinum toxin to other types of neuropathic pain and to better understand its mechanisms of action, we believe that our study offers promising new therapeutic perspectives for botulinum toxin.5 The last comment from Torgovnik and colleagues concerns our relationship with Allergan. On one occasion in 2004, Danièle Ranoux received an honorarium from Allergan in the amount of 2,500 euros for an educational program regarding the respective potencies of botulinum toxin (Botox) and BTX-A (Dysport) on muscle tone.6 The last contact she had with Allergan was in 2006 concerning a study of the clinical differences between various botulinum toxin formulations, which was published in a supplemental issue of European Journal of Neurology,7 sponsored by an unrestricted education grant from Allergan.7 Dr Ranoux did not receive honoraria for this publication. Although we mentioned in our article1 that Allergan supplied the BTX-A that was used in the study, we neglected to disclose this previous relationship with Allergan because the honorarium in question was totally unrelated to the study published in Annals, and we do not believe that this past relationship could constitute a potential conflict of interest or source of bias for the current study, which used an appropriately controlled and blinded design. To be clear, we did not receive support from Allergan in any aspect (ie, financial, study design, statistical analysis, manuscript writing, or data management) for the study published in Annals,1 which was made possible through a collaboration between Danièle Ranoux, a botulinum toxin specialist, and Institut National de la Sante et de la Recherche Médicale neurologists and pain specialists. Editors note: The editors recognize that standards for disclosures of potential conflicts of interest cannot be codified easily to fit all possible situations; however, we have initiated a policy requiring acknowledgment of all financial ties to forprofit organizations whose products are in any way related to the study submitted to Annals. The editors consider any such relationship a conflict of interest if it took place within 2 years of the initiation of the study.

P01-156 Estimation of placebo effect in therapy of generalized anxiety disorder

Studying of placebo response in patients with Generalized Anxiety Disorder (GAD) was the aim of research. 90 patients (68 female, 22 male, mean age of 33 years) were studied. All patients accepted inactive placebo (P) within 7 days and then - Alprazolam (A) in a dose of 1-3 mg per day within 4 weeks. Efficacy of treatment was estimated weekly by the HAM-A scale. After week of placebo reception, patients with HAM-A score < 9 made group of remission (R), with ≥50% HAM-A reduction - placebo responders group (PR), with HAM-A reduction 25-49% - partial placebo responders group (PPR), ≤ 25% HAM-A reduction - placebo nonresponders group (PNR).After week of reception placebo 16.6% of patients HAM-A made group R, 26.7% - PR; 30% - PPR, 26.7% - PNR. After active therapy (A) Therapeutic Remission group (RT - HAM-A score < 9) consisted of 100% of group R, 75% of PR, 81.5% of PPR and 8,33% of PNR. 25% of PR, 18% of PPR and 8.33% of PNR became Therapeutic Responders (TR - HAM-A reduction >50%). Partial Therapeutic Responders (PTR - HAM-A reduction 25-49%) and Therapeutic Nonresponders (TNR ≤ 25% HAM-A reduction) consisted only of PNR (62.5% and 20.83%).Absent response on (P) frequently correlated with low efficacy of therapy of (A). High positive placebo effect (PE) was defined in patients in whom improvement after transferring on active therapy became even more expressed. The received data allow to consider presumably PE like predictor of efficacy of benzodiazepines therapy for GAD.

Double-blind, placebo-controlled trial with esomeprazole for symptoms and signs associated with laryngopharyngeal reflux

To determine the efficacy of proton pump inhibitor (PPI) therapy with esomeprazole on symptoms and signs associated with laryngopharyngeal reflux (LPR). Prospective, double-blind, randomized, placebo-controlled study. Sixty-two patients with a reflux finding score (RFS)>7 and a reflux symptom index (RSI)>13 were enrolled and received either esomeprazole 20 mg twice daily or placebo for three months. RSI and RFS were assessed at baseline, after six weeks, and after three months. Reductions of total RSI and RFS as well as of several subscores were significantly higher in the treatment group compared to placebo after three months (P<0.05 each). The difference between study groups was most pronounced for posterior commissure hypertrophy (P<0.01). In the treatment of LPR-related symptoms a high placebo effect can be observed. However, compared to control, twice-daily PPI treatment for three months demonstrated a significantly greater improvement in laryngeal appearance and LPR symptoms.

Lack of efficacy of alpha-lipoic acid in burning mouth syndrome: A double-blind, randomized, placebo-controlled study

Background: A systematic review from the Cochrane Collaboration stated that alpha-lipoic acid (ALA) may help in the management of burning mouth syndrome (BMS). Because all of the data on ALA came from a single group, it has been stressed that its effectiveness should be reproduced in other populations. Aim: A double-blind, randomized, placebo-controlled study, including two test groups (Group A and Group B) and one control group (Group C), was carried out to evaluate the efficacy of systemic ALA (400 mg) and ALA (400 mg) plus vitamins in the treatment of BMS. Methods: Sixty-six patients (54 females and 12 males) were included in an 8-week trial. Symptoms were evaluated by using a visual analogue scale (VAS) and the McGill Pain Questionnaire (MPQ) at 0, 2, 4, 8 and 16 weeks. Results: Fifty-two patients (43 females and 9 males, aged 67.3 ± 11.9 years) completed the study. All three groups had significant reductions in the VAS score and in the mixed affective/evaluative subscale of the MPQ; the responders’ rate (at least 50% improvement in the VAS score) was about 30%. No significant differences were observed among the groups either in the response rate or in the mean latency of the therapeutic effect. Conclusions: The fairly high placebo effect observed is very similar to data obtained from patients affected by atypical facial pain. This study failed to support a role for ALA in the treatment of BMS, and further investigations are needed to identify the cause of BMS in order to develop efficacious therapies.

Experts Dispute Report Critical of Antidepressants

Experts Dispute Report Critical of Antidepressants