***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: OBJECTIVE It has been proposed that 50%-75 % of the efficacy of antidepressant medication represents the placebo effect , since many depressed patients improve when treated with either medication or placebo . This study examined brain function in depressed subjects receiving either active medication or placebo  and sought to determine whether quantitative electroencephalography ( QEEG ) could detect differences in brain function between medication and placebo responders . Both QEEG power and cordance , a new measure that reflects cerebral perfusion and is sensitive to the effect of antidepressant medication , were examined . METHOD Fifty-one subjects with major depression were enrolled in one of two independent , 9-week double-blind , placebo-controlled studies in which either fluoxetine ( N=24 ) or venlafaxine ( N=27 ) was the active medication . Serial QEEG recordings were performed during the course of treatment . After 9 weeks , the blind was broken and subjects were classified as medication responders , placebo responders , medication nonresponders , or placebo nonresponders . RESULTS No significant pretreatment differences in clinical or QEEG measures were found among the four outcome groups . Placebo responders , however , showed a significant increase in prefrontal cordance starting early in treatment that was not seen in medication responders ( who showed decreased cordance ) or in medication nonresponders or placebo nonresponders ( who showed no significant change ) . There was no significant change in QEEG power during treatment . CONCLUSIONS These findings suggest that " effective " placebo treatment induces changes in brain function that are distinct from those associated with antidepressant medication . If these results are confirmed , cordance may be useful for differentiating between medication and placebo responders Background The reasoning behind evaluating medical interventions is that a hierarchy of methods exists which successively produce improved and therefore more rigorous evidence based medicine upon which to make clinical decisions . At the foundation of this hierarchy are case studies , retrospective and prospect i ve case series , followed by cohort studies with historical and concomitant non-r and omized controls . Open-label r and omized controlled studies ( RCTs ) , and finally blinded , placebo-controlled RCTs , which offer most internal validity are considered the most reliable evidence . Rigorous RCTs remove bias . Evidence from RCTs forms the basis of meta-analyses and systematic review s. This hierarchy , founded on a pharmacological model of therapy , is generalized to other interventions which may be complex and non-pharmacological ( healing , acupuncture and surgery ) . Discussion The hierarchical model is valid for limited questions of efficacy , for instance for regulatory purpose s and newly devised products and pharmacological preparations . It is inadequate for the evaluation of complex interventions such as physiotherapy , surgery and complementary and alternative medicine ( CAM ) . This has to do with the essential tension between internal validity ( rigor and the removal of bias ) and external validity ( generalizability ) . Summary Instead of an Evidence Hierarchy , we propose a Circular Model . This would imply a multiplicity of methods , using different design s , counterbalancing their individual strengths and weaknesses to arrive at pragmatic but equally rigorous evidence which would provide significant assistance in clinical and health systems innovation . Such evidence would better inform national health care technology assessment agencies and promote evidence based health reform & NA ; Patient , provider , and clinical investigator expectations concerning treatments are believed to play important roles in patient response . This study examined the association of patient and research nurse/physician pretreatment expectations of pain relief with actual pain relief , the accuracy of patient and research nurse guesses about patient medication assignment , and changes in research nurse and patient pain relief expectations over the course of a r and omized double‐blind trial of amitriptyline versus an active placebo for patients with chronic pain and spinal cord injuries ( SCI ) . Patient expectations of pain relief with amitriptyline were associated significantly with actual pain decrease for patients in the  amitriptyline  , but not placebo , condition . Research nurse/physician expectations did not predict patient pain relief . Both patients and the research nurse were able to guess patient medication assignment at a rate significantly greater than chance . The research nurse 's , but not the patients ’ , expectations of pain relief with amitriptyline decreased significantly over the course of the study . These findings have implication s for future r and omized controlled trials . Fully double‐blind conditions are very difficult to achieve , and it is informative to assess patient and research clinician expectations and guesses regarding medication assignment Background 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 r and omised , 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 . Methods 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 . Results 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 . Conclusion 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 . Trial Registration International Clinical Trials Registry IS RCT N98972974 We investigated the mechanisms underlying the activation of endogenous opioids in placebo analgesia by using the model of human experimental ischemic arm pain . Different types of placebo analgesic responses were evoked by means of cognitive expectation cues , drug conditioning , or a combination of both . Drug conditioning was performed by means of either the opioid agonist morphine hydrochloride or the nonopioid ketorolac tromethamine . Expectation cues produced placebo responses that were completely blocked by the opioid antagonist naloxone . Expectation cues together with morphine conditioning produced placebo responses that were completely antagonized by naloxone . Morphine conditioning alone ( without expectation cues ) induced a naloxone-reversible placebo effect . By contrast , ketorolac conditioning together with expectation cues elicited a placebo effect that was blocked by naloxone only partially . Ketorolac conditioning alone produced placebo responses that were naloxone-insensitive . Therefore , we evoked different types of placebo responses that were either naloxone-reversible or partially naloxone-reversible or , otherwise , naloxone-insensitive , depending on the procedure used to evoke the placebo response . These findings show that cognitive factors and conditioning are balanced in different ways in placebo analgesia , and this balance is crucial for the activation of opioid or nonopioid systems . Expectation triggers endogenous opioids , whereas conditioning activates specific subsystems . In fact , if conditioning is performed with opioids , placebo analgesia is mediated via opioid receptors , if conditioning is performed with nonopioid drugs , other nonopioid mechanisms result to be involved Background The total effect of a medication is the sum of its drug effect , placebo effect ( meaning response ) , and their possible interaction . Current interpretation of clinical trials ' results assumes no interaction . Demonstrating such an interaction has been difficult due to lack of an appropriate study design . Methods 180 adults were r and omized to caffeine ( 300 mg ) or  placebo  groups . Each group received the assigned intervention described by the investigators as caffeine or placebo , in a r and omized crossover design . 4-hour-area-under-the-curve of energy , sleepiness , nausea ( on 100 mm visual analog scales ) , and systolic blood pressure levels as well as caffeine pharmacokinetics ( in 22 volunteers nested in the caffeine group ) were determined . Caffeine drug , placebo , placebo-plus-interaction , and total effects were estimated by comparing outcomes after , receiving caffeine described as placebo to receiving placebo described as placebo , receiving placebo described as caffeine or placebo , receiving caffeine described as caffeine or placebo , and receiving caffeine described as caffeine to receiving placebo described as placebo , respectively . Results The placebo effect on area-under-the-curve of energy ( mean difference ) and sleepiness ( geometric mean ratio ) was larger than placebo-plus-interaction effect ( 16.6 [ 95 % CI , 4.1 to 29.0 ] vs. 8.4 [ -4.2 to 21.0 ] mm*hr and 0.58 [ 0.39 to 0.86 ] vs. 0.69 [ 0.49 to 0.97 ] , respectively ) , similar in size to drug effect ( 20.8 [ 3.8 to 37.8 ] mm*hr and 0.49 [ 0.30 to 0.91 ] , respectively ) , and its combination with the later was larger than total caffeine effect ( 29.5 [ 11.9 to 47.1 ] mm*hr and 0.37 [ 0.22 to 0.64 ] ) . Placebo-plus-interaction effect increased caffeine terminal half-life by 0.40 [ 0.12 to 0.68 ] hr ( P = 0.007 ) . Conclusions Drug and placebo effects of a medication may be less than additive , which influences the interpretation of clinical trials . The placebo effect may increase active drug terminal half-life , a novel mechanism of placebo action . Trial Registration Clinical Trials.gov identification number - NCT00426010 TOC summary The 50 % likelihood of receiving a drug or placebo in clinical trials modifies the outcome , an effect strongly modulated if minor onset sensations are associated with drug intake . ABSTRACT The knowledge of having only a 50 % chance of receiving an active drug can result in reduced efficacy in blinded r and omized clinical trials ( RCTs ) compared to clinical practice ( reduced external validity ) . Moreover , minor onset sensations associated with the drug ( but not with an inert placebo ) can further challenge the attribution of group differences to drug‐specific efficacy ( internal validity ) . We used a r and omized experimental study with inert placebos ( inert substance ) vs active placebos ( inducing minor sensations ) , and different instructions about group allocation ( probability of receiving drug : 0 % , 50 % , 100 % ) . One hundred forty‐four healthy volunteers were informed that a new application method for a well‐known painkiller would be tested . Pain thresholds were assessed before and after receiving nasal spray . Half of the nasal sprays were inert placebos ( sesame oil ) , while the other half were active placebos inducing prickling nasal sensations ( sesame oil with 0.014 % capsaicin ) . The major outcome was pain threshold after placebo application . A substantial expectation effect was found for the inert placebo condition , with participants who believed they had received an active drug reporting the highest pain thresholds . Active placebos show substantial differences to passive placebos in the 50 % chance group . Therefore , patient expectations are significantly different in placebo‐controlled clinical trials ( 50 % chance ) vs clinical practice ( 100 % chance ) . Moreover , minor drug onset sensations can challenge internal validity . Effect sizes for these mechanisms are medium , and can substantially compete with specific drug effects . For clinical trials , new study design s are needed that better control for these effects A number of pharmacologic treatments examined in recent r and omized clinical trials ( RCTs ) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated . Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies , such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo ( “ assay sensitivity ” ) . Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development . Therefore , an Initiative on Methods , Measurement , and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was review ed and discussed . On the basis of this meeting and subsequent discussion s , the authors recommend consideration of a number of patient , study design , study site , and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments . Increased attention to and research on method ological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence ‐based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety There is ongoing debate about whether r and omized , placebo-controlled trials under a double-blind have reliably established the pharmacological efficacy of antidepressants . Numer 
    Output:
    
Although this study examined placebo effects and not the whole placebo response as in r and omised controlled trials , it does suggest that the additivity assumption may be incorrect , and that the estimated drug effects in r and omised controlled trials may be underestimated , particularly in studies reporting large placebo responses .