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“I am not interested in any research that is not randomized, blinded and includes a control group” was stated recently to a group of colleagues at a clinical meeting; another colleague at a different institution made a similar statement and added the caveat “… and has large numbers”.
These statements are promoted and supported by the institutions training our health professional clinicians – it is idealist and reflects a perfect world. These large-scale, randomized, blinded, control group studies are usually designed to address an already-identified issue and examples include incidence, prevalence, and treatment strategies for health problems such as heart disease, diabetes, dementia, etc.
Whilst idealistic, it is also very limiting in the research read and the issues addressed – what do these clinicians do if there aren’t any large-scale, randomized, blinded, controlled studies addressing an issue of concern?
In practice, our initial red flags seem to be case studies – an issue has been identified, a number of treatment strategies trialled until an effective one is identified, and then the case and its findings is published to advise other clinicians of an effective treatment strategy with that combination of circumstances; and this usually includes the underlying reasons as to why different strategies did not, and ultimately did, prove effective.
Once a number of case studies on a particular issue are published, then there is often a small research project evaluating the effectiveness of the trialled treatment strategies – and usually they are randomized, have a control group and are typically blinded.
There are two classic examples supporting this research process
Excessive zinc-induced copper-deficiency myeloneuropathy. A case study identified a person with copper-deficiency myeloneuropathy and found the copper deficiency was induced by an excessive zinc intake; the source of zinc was denture cream. Subsequently a number of other similar case studies were published supporting the initial finding, and finally a small study was conducted that also supported the initial finding.
Many denture creams now do not contain zinc, and the finding is an accepted form of copper deficiency causation.
It is unlikely this issue will ever attract the gold-standard research criteria of being randomized, control group, blinded, and large numbers.
Proton pump inhibitor induced magnesium deficiency. As a consequence of a case study by two Australian clinicians, who found that a specific proton pump inhibitor interfered with magnesium availability, a plethora of case studies with similar findings have subsequently been published.
We are now at the stage whereby contradictory evidence is being published – which causes confusion at best. Do we need further research to clarify both causation and treatment? – certainly; is it likely to be conducted? – perhaps; will it attract large trial support? – unlikely.
What will these clinicians do if there aren’t even any case studies or small research projects to refer to?
If there is no research - and the rarer the clinical issue the more likely there will be very limited available evidence, regardless of quality of the evidence - then our determinations must be guided by first principles
Will doing nothing cause harm?
Will the intervention cause more harm than benefit?
Will the intervention confer benefit?
As an example of this I recently assessed an “old” person (aged 60+ years) with MELAS Syndrome (Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes Syndrome) which is an inherited Inborn Error of Metabolism. Most of the available research was case-study based, mostly n = 1, and mostly on children.
The case studies guided treatment direction, and application of first principles was necessary to underpin the decisions being made:
Will doing nothing cause harm? – yes, as the harm caused by the disorder would continue to progress relatively rapidly; effective treatment is likely to stabilise the condition and slow or stop progression;
Will the proposed interventions cause more harm than benefit? – unlikely, based on case study findings;
Will the proposed interventions confer benefit? – most likely, based on case study evidence, especially if it is sufficiently effective to slow or stop progression.
MELAS Syndrome raises both nutrition and pharmacological issues – and a combination of both. The subject of my “case study” was prescribed a number of drugs with seriously compromising nutritional consequences such as
inhibition and uncoupling of oxidative phosphorylation – typically related to aspirin, and includes other drugs,
CoQ10 depletion – typically related to statins,
inhibition of carnitine transport and uptake – includes drugs such as verapamil, carbamazepine, cefepime, cimetidine, clonidine, gabapentin, lamotrigine, quinine bisulphate, quinine sulphate, sodium valproate, thyroxine, tiagabine, topiramate, verapamil, vigabatrin, zidovudine.
Would these clinicians have maintained the status quo? – hopefully not as it contravenes the first of the first principles, ie doing nothing will cause harm.
The nutritional consequences of the pharmacological intervention are an excellent example of application of case study research and application of clinical first principles, as well as being an example of a health issue that will not attract large-scale, randomized, blinded, control-group-based research.
I do hope most of our current and future clinicians, academics and scientists will be more broadminded in their scientific readings than the two clinicians I refer to.