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The thinking doctor’s guide to placebos

BMJ 2008; 336 doi: (Published 01 May 2008) Cite this as: BMJ 2008;336:1020

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The thinking doctor’s guide to very low doses

Pittrof and Rubenstein make a clear and convincing argument for the potential value of placebos. However, I would like to suggest an approach that would likely get almost all, if not more of the value of what one could get by using placebos, but eliminate almost all the ethical and other issues associated with the use of placebos. It is an approach I, and a number of colleagues, have been endorsing for years. The approach is starting with “very” low doses of medications. While many clinicians obviously endorse the “start low, go slow” approach, in my experience, this usually means starting with the lowest available dose (or at best maybe ½ that dose). So first off, “very” low dose needs to be defined.

1) I am not talking about homeopathic doses – that’s a whole other topic.

2) As mentioned above, I am also not talking about starting with the lowest marketed dose – I am talking typically about a ¼ to an 1/8 or sometimes even less of the lowest marketed dose of a medication.

A few of the many principles on which this approach is based are as follows:

1) For the clear majority of conditions seen in family practice (insomnia, depression, elevated blood pressure, mild depression, mild asthma, anxiety, osteoarthritis, menopausal symptoms etc) there is rarely a hurry to get a response.

2) For many marketed drugs (especially when they first come on the market) the recommended starting doses are too high [1]

3) The initially marketed dose, is a dose that by design works for most people. Clinicians need to be aware when drugs are put on the market, very rarely have doses on the true lower end of the dose response curve been studied.

4) The placebo group response for many conditions is in the 20-40% range.

5) Almost all side effects of drugs are dose related.

6) If you look at dose response curves for drugs, they are NOT typically effect vs dose but rather effect versus the LOG of the dose. This explains why you rarely lose much effect by cutting the dose in half.

7) We have all had patients come and tell us that for side effect or cost issues they are using just ¼ of the tablet we initially suggested and it works just fine.

8) In animal research (virtually genetically identical rats) there are clear dose response relations. Relatively, humans are genetic mongrels so the dose response is obviously even more variable. There really is no way a clinician can tell how a patient will respond to a drug or how they will metabolise a drug etc

A few of the many examples for low if not very low doses include:

1) 50-200 mg of HCTZ used to be the recommended daily dose - 12.5 mg is the typical starting dose now – 6.25 mg or even lower should be the maximum initial starting dose

2) A ¼ of the dose of Viagra works as well as a full dose – why not try even lower doses?

3) When sumatriptan (Imitrex) first came on the market the dose was 100 mg. We now know 25 mg and 50 mg works pretty much as well as100 mg - is there any reason why 12.5 mg or 6.25 mg shouldn’t be considered?

4) Fluoxetine (Prozac) 5 mg daily has been shown to have an effect - why not start with 2.5 or 1.25 mg daily [2].

5) One excellent recent example is ezetimibe (Ezetrol/Zetia). While one can debate whether or not this drug does anything to cardiovascular disease I bet very few clinicians are aware of the fact that 0.25 mg (1/40th of the recommended initial staring dose of 10 mg) provides 50% of the LDL lowering effect [3]. The recommended starting dose (10 mg) for ezetimibe has little to do with what is actually the best starting dose, but much more on regulatory and drug company issues.

Some of the discussion with patients that is needed if one wishes to try very low doses includes the following:

1) There is no urgency to the treatment

2) We really have no idea what dose will work for you.

3) The typical recommend starting doses are too high.

4) Starting with ¼ to an 1/8 of the dose should considerably decrease the chance of side effects.

5) You (the patient) will determine the correct dose.

6) After a while, if you get a good response, we will reassess the whole issue because there is no way to really tell if you got better because of the drug or because of the placebo and/or tincture of time effect. We sometimes say to the patients they should – half-jokingly obviously - for the first few days just look at the tablet; if the problem isn’t improving, then lick the tablet every day for a week or so and see how that goes. Then if that doesn’t work, start taking an 1/8 of a tablet a day and so on. This low dose approach (as well as the placebo approach) obviously does not apply to acute life-threatening conditions or conditions for which a therapeutic effect/endpoint cannot easily be determined – or example reduction in seizures in a patient who only has seizures 1-2 times a year.

Some obvious advantages of this very low dose approach are:

1) There is no deception.

2) The patient is completely engaged in the process, and in my experience, really buys into the concepts of “just a little bit to start off with”.

3) Cost savings can be considerable.

4) Almost all drug interactions can be avoided

Some dose cutting tips

1) Not all drugs come in dosage forms that allow small doses to be used – however the vast majority of tablets can be split especially if one uses a pill cutter. One doesn’t need to be too spastic that every piece is exactly the same size.

2) Some capsules can be opened or potentially, as for instance the proton pump inhibitors, the frequency of the dosing could be increased – instead of daily go to ever 2-3 days etc.

3) Many drugs do come in a liquid form - fluoxetine for instance is available as a 20 mg/5 ml liquid dosage form so doses of just a few mg could easily be used.

1. Cohen JS. Over Dose: The Case Against the Drug Companies: Prescription Drugs, Side Effects, and Your Health, 2001 2. N Engl J Med. 1994;331:1354-61 3. Clin Ther 2001;23:1209-30

Competing interests: None declared

Competing interests: No competing interests

08 May 2008
James P McCormack
Professor, Faculty of Pharmaceutical Sciences, Therapeutics Initiative, UBC, Vancouver, BC, Canada