common placebos are usually inert tablets or sham surgery based on false information . since the publication of
henry k. beecher 's in 1955 , the phenomenon has been considered to be clinically important .
placebo effects were shown to be genuine psychobiological events attributed to the overall therapeutic context . from a psychological point of view , many mechanisms might contribute to placebo effects , including expectations , conditioning , learning , motivation , memory , reward and anxiety reduction , etc .
apparent benefits of a new drug may derive from the placebo effect but not from the drug per se .
therefore , modern clinical trials control for this effect by using a placebo , in which the subjects are blinded as to whether they receive a drug treatment or a placebo . in this way
, placebo - controlled trials might provide information about the real effectiveness of a drug .
the view of placebo effect was notably challenged when a systematic review of clinical trials in 2001 concluded that there was no evidence of clinically important effects , except perhaps in the treatment of pain and other continuous subjective outcomes . since evidence - based medicine ( ebm )
is increasingly emphasized , placebo is still widely used in clinical trials other than in the treatment of pain and continuous subjective outcomes .
currently , international journals as well as clinical researchers are inclined to avoid or even ignore the ethical aspects of placebo .
however , accumulating ethical concern has arisen from the worldwide use of placebo in randomized control trials ( rcts ) , because the investigators in a certain trial may render its participants without early and optimal treatment . where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm .
( extracted from the declaration of helsinki ) a recent study , the european cooperative acute stroke study iii ( ecass iii ) reported by bluhmki et al and by hacke et al supported the use of alteplase three hours after the onset of stroke symptoms , while together with other studies , ecass iii raised some concerns about thrombolytic studies . despite repeated emphases of early treatment on acute ischemia , the control group in ecass iii failed to receive any treatment except the placebo .
the lack of evidence - based therapies should not justify the exclusion of empirical use of anti - platelet agents , or others . in this regard ,
it is almost always the case in china , since traditional chinese medicine has been a routine for patients suffering from cerebrovascular ischemia .
another example of clinical trial that may raise ethical concerns is the one conducted by kappos , et al , about oral fingolimod in treating relapsing multiple sclerosis ( ms ) .
this placebo - controlled trial revealed that fingolimod improved the relapse rate , the risk of disability progression , and end points on mri .
however , the longer the trial lasts , the longer the patients in the placebo group must go without treatment . in this context
, the well - acknowledged and widely used therapeutic approaches should be considered first and foremost as controls , when rcts are designed .
although placebos may be helpful in treating ms , the better - acknowledged ways such as interferon - beta and glatiramer acetate can potently alleviate the sufferings of patients with ms and can readily serve as positive controls in that study . as a clinician ,
the sanctification of placebo is partly due to the repeated emphasis of rcts as the gold standard of clinical trials .
dichotomy seems necessary in evaluating the role of placebo in scientific research ; the need for placebo - controlled design can not be denied at certain stage of drug development , whereas for larger phase iv studies , better alternatives should be considered .
ethically , the clinicians are always expected to provide their patients with the best choices of treatment other than placebo , and the best available treatment as a positive control other than placebos is preferable to the patients . in neurological field , for example , aspirin is widely accepted as a control in trials with regard to prevention or treatment of cerebral ischemic disorders , because its prophylactic as well as therapeutic effects on cardiovascular events are well established .
although the control group is a must in rcts , an alternative way such as a delayed - start approach , can be utilized to avoid ethical issues that may arise .
delayed - start studies are designed primarily to test the disease - modifying effect of a drug , whereas they can reduce the ethical concerns that patients in the placebo group must go without treatment until the end of the study .
the control subjects enrolled in the aforementioned thrombolytic study should at least start to accept conventional medication therapies immediately after the time - window for thrombolytic studies .
similarly , clinicians should always bear in mind that no treatment equals killing for their patients .
clinicians / researchers need to understand the implications of offering no treatment in certain situations before enrolling experimental subjects .
more importantly , a thorough explanation about the aforementioned possible implications should be performed by the clinicians .
the placebo effect is produced on the premise that the subjects believe the effectiveness of placebo .
this is different from the practice in rcts in which the subjects are informed of the possibility of accepting only a sham medical intervention .
informed consent for a study is usually required to be considered ethical , including the disclosure that some patients are to receive placebos only . in this case , the subjects do not know whether they might be getting a real treatment or a sham one , and thus might suspect the efficacy of the medical interventions even before the trials . as a result , placebos do not work as strongly in clinical trials , as in basic research .
what 's worse , the deception involved in the use of placebos creates conflicts between the hippocratic oath and the honesty of the doctor 
the purpose of the clinical trials should be explained in detail in the process of obtaining informed consent from the participants , while it is not always the case , especially in low - income countries . for patients in low - income countries ,
the participation in clinical trials is intriguing simply because poor patients have the chance of getting free treatment , or they can get rewards for attending the research .
this may lead to selection bias as well as ethical debates because the poor participants have no better choice than attending the trials .
the honest relationship between doctors and patients is further worsened because of the notion of the patients that they are utilized . in summary , although the ethics of placebos have been debated frequently in history , even in the revision process of the declaration of helsinki , placebos have given rise to ethical debates much more often than ever before . as the pilgrimage of placebo is still on the way , refinement of controls in rcts
 a placebo is a sham medical intervention that can produce a placebo effect . 
 laboratory evidence supports the existence of several mechanisms of placebo effects in both healthy population and patients with a variety of medical conditions . 
 the ethics of placebos have long been debated . however , accumulating ethical concern has arisen from the worldwide use of placebo in randomized control trials ( rcts ) , which may render their participants without early and optimal treatment . although the pilgrimage of placebo is still on the way , refinement of controls in rcts is worth paying new attention to . 
Introduction