Overrated Medications Series: No. 4 Cholinesterase Inhibitors for Alzheimer’s Dementia

Alzheimer’s dementia is a tragic disease and there is no effective treatment for it.  Families watch their loved ones become more confused, initially suffering short-term memory loss, then long-term memory loss and finally becoming withdrawn and requiring total care.  Eventually patients stop eating and drinking.  Along the way many patients become irritable, even violent.  Others are docile.  Alzheimer’s dementia is a terminal illness and care is palliative.  Doctors want to help, offer some hope to families and patients.  For that reason they prescribe cholinesterase inhibitors.

Neurons (Nerve Cells) in the brain are separated by very small spaces known as synapses.   Acetylcholine  is a chemical used by neurons to communicate across synapses.  In Alzheimer’s dementia, there is reduced acetylcholine activity due to damage or death of cholinergic neurons.   So, according the cholinergic hypothesis of Alzheimer’s dementia, increasing acetylcholine will slow the progression of Alzheimer’s dementia.  Cholinesterase inhibitors increase acetylcholine by inhibiting the enzyme that breaks down acetylcholine.   Examples of these drugs are Aricept (donepezil) and Exelon (rivastigmine).

This class of drugs work.  They work so poorly that not once, never as long as I have prescribed them over more than 10 years, do I remember a patient or their family coming in and telling me  that they have noticed any improvement in Alzheimer’s symptoms.   I do not recall any physician telling me of their fondness for cholinesterase inhibitors.   Normally I would not rely on anecdotal evidence;  it is the worst kind of evidence.   In this case I think 10 years, no success, is enough evidence.  However, since I am a simple country doctor my readers will ask for a bit more evidence.  Keep reading.

Here is the abstract from an article from The Lancet titled Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial.  This study showed not even a 1 point change in the Mini-mental Status Exam Score with 2 years of Aricept use.   No significant benefit in institutionalization or progression of disability.  Compared with placebo Aricept offered no differences in psychological outcomes, deaths or adverse events.  The article’s interpretation “Donepezil is not cost effective, with benefits below minimally relevant thresholds. More effective treatments than Cholinesterase inhibitors are needed for Alzheimer’s disease”.

A systematic review of the clinical trials of the cholinesterase inhibitors is found in the British Medical Journal.  The conclusion of the authors: “Because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer’s disease is questionable.”  This review article pointed out that these medications do in fact work, but that their effect is not clinically relevant.  Quoting from the article:  “The gains of 1.5-3.9 points in cognitive function, as measured with the Alzheimer’s disease assessment scale, fall below the 4 points that a panel of experts from the US Food and Drug Administration proposed as the minimum of a clinically important effect.”

Given these drugs poor efficacy, why are they prescribed?  I think it is because the pharmaceutical industry markets them well.   Doctors want to do something to help and there is really nothing else to offer.

Now the risks.  The risks it seems are increased chance of permanent pacemaker insertion, syncope and hip fractures in the elderly.  The risk was small and amounted to less than 3% increased risk per 1000 person-years for each event mentioned.  This was also an observational study and so there may be, in fact, no risk of these things.  But for such poorly beneficial drugs, should any risk be tolerated?

I will leave you with costs.  After all, if these medications are cheap enough, perhaps we would give them a try.

Aricept 10 mg  $2871.60 for 1 years therapy.

Exelon Patch 9.5 mg / 24 hours  $2770.68 for 1 years therapy.

Prices taken from Epocrates.com on 4/22/2010.