Clinical trials - what do we mean by 'no-effect'?

This is a more difficult question than one might think.  The traditional randomised controlled trial (RCT) randomly selects people from a population of interest; then randomly allocates them to one of two or more treatments, one of which may be a placebo or 'dummy' drug.  The purpose of the placebo is to account for the beneficial (or sometimes detrimental) effect that one sometimes gets just through being given a treatment irrespective of whether it works or not.  So far so good..but..

There is a problem.  In most cases the actual clinical treatment options are not new drug versus dummy drug; but new drug versus some other treatment, which may be something or it may be nothing.  New drug versus dummy drug is almost never the actual option given to patients.  Imagine the conversation with your doctor, "the treatment for condition XXX currently is a drug which we think is of no benefit apart from the fact that it tastes nice and comes in a fancy bottle". 

Traditionally the effect that is seen just by being given something has been termed the 'placebo' effect, Latin for 'I shall please'.  This is a link to the Wikipedia page, (but I did actually know the Latin bit).  In some circumstances the pacebo can be a problem, for example if people just feel better without getting better they may miss treatment that they need.  In studies if they feel better from being given a placebo it may hide a benefit from the active drug (this is termed a Type II error - missing a beneficial effect from a treatment).  There are also ethical issues about people not understanding what they are taking.

However, where the desired outcome is comfort, maybe anything that provides comfort is ok, and if that is a placebo maybe that does not matter.  This may, for example be the case in the treatment of children with a fever, where the desired outcome of treatment is not temperature reduction but relief of discomfort.  If a medicine looks nice, tastes nice, and reduces anxiety in parents and children does it actually matter if it is the active ingredient or a placebo effect?

The reason why this is topical now, is that there is a paper in JAMA Pediatrics which looks at this very subject in the treatment of autism, finding a strong placebo effect compared to the active treatment, indeed in some groups the placebo group actually did better.  Puzzling.. 

What to make of this?  Firstly don't underestimate the power of the placebo - it may be as simple as someone taking an interest in the patient making them feel better.  Secondly, as educated informed consumers of research always check, when comparisons are made, to what was the new treatment being compared?  This brings us to a wider point of efficacy v effectiveness - efficacy is can it work in ideal circumstances (as one would see in a RCT) while effectiveness is does it work in practice? - These are often not the same.  Check to see if your new treatment works outside of the lab!

King et al JAMA Pediatr. Published online September 23, 2013. doi:10.1001/jamapediatrics.2013.2698

Are children really 'little adults'?

One of the phrases that trips off of the tongue of most paediatric nurses is that ‘children are not little adults’, but a recent review in Archives of Disease in Childhood looking at drug dosing in children suggests that in this regard at least, they may be.  There are two crucial concepts in pharmacology, these being pharmacokinetics (PK), which is what the body does to the drug; and pharmacodynamics (PD), which is what the drug does to the body.  The other important issue of course is the desired effect and how this balances against undesirable effects.

The authors suggest that the per Kg doing method probably results in under-dosing of many children, particularly those in the 1-3 year-old age group who have relatively high drug clearance and metabolic rates. Furthermore the relationship between drug clearance and weight is not linear, which may be problematic particularly among obese children as the role that fat plays in drug distribution and clearance differs between different drugs.  As if that weren’t enough, there is a third method of assessing maturity, while we are used to thinking of age and weight; the passage of time, (defined as the postmenstrual age) may also be useful measure as this takes account of maturation before birth.  All of this leads the authors to conclude that children over the age of 2 years are indeed probably adult-like (yes ‘little adults’) differing only in size; while those under this age, being less mature are immature children.

All of this is rather confusing for the clinical nurse, so what should be done.  Firstly there is everyone’s favorite dissertation recommendation – more research.  More immediately it may be possible to individualise doses more, taking into account specific covariates, although this may require computer support to allow for the more complex calculations and decision making processes.  

However, there is something that everyone can do right now, which is to make treatments explicitly outcome-based, taking into account the benefits and risks of treatments.  The authors of the papers give a good example, which is that of opiate analgesia, how specific children may balance the relative importance of pain control and nausea; some might think the first is more important, others might put up with a bit of pain in order not to feel nauseated.  The treatment of fever presents another such challenge, what outcome should be aimed for in the treatment of fever with antipyretics, bearing in mind fever is a symptom not a disease; it does not need treating and may even be helpful?    

Along with ‘children are not little adults’, another phrase I remember from my student days was the four rights right patient, right drug, right dose, right time; maybe we should add a fifth – right outcome?