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For years, we and others have advocated
starting treatment of chronic indolent con-
ditions at doses lower than those typically
recommended in the product monographs.1The
approach we recommend is to use a very low
dose when starting a new medication if the con-
dition is not life-threatening or producing severe
symptoms. Unfortunately, this approach is not
used that much in practice.
First, we should define “very low dose.” The
“start low, go slow” approach when starting
medications — which entails starting with the
lowest available dose — is generally well ac -
cepted in the medical community, especially for
elderly pa tients. However, our approach is dif-
ferent. We are suggesting that it is reasonable in
many cases to start with half the lowest marketed
dose for older, established products. For newly
marketed medications, we suggest starting with
half or even one-quarter the lowest available
dose, because dose–response studies have either
not been done or their findings have not been
incorporated into the product monograph. In
addition, often only one or maybe two doses are
marketed initially.
Our approach has several important advan-
tages over the use of initial doses recommended
in many product monographs. The use of a very
low starting dose (a) would further decrease the
risk of adverse effects; (b) engage patients in
determining the best dose for them; and
(c) would still provide a placebo effect, if pre-
sent, and mitigate the ethical issues associated
with the use of placebos.
Rationale
This very-low-dose approach is based on all
three pillars of evidence-based practice: evidence
from clinical trials, clinical experience and
patient preference.
For most conditions seen in general practice
(e.g., insomnia, elevated blood pressure, mild
depression, chronic ob structive lung disease, anxi-
ety, osteoarthritis, menopausal symptoms, ele-
vated cholesterol and elevated glucose), an imme-
diate response to drug treatment is rarely needed.
For many marketed drugs, especially when
originally launched, the recommended starting
doses are too high.2By design, initially marketed
doses are ones that work for most patients. How-
ever, many of those same patients might benefit
equally from lower doses. Rarely have doses on
the true lower end of the dose–response curve
been studied when drugs are first marketed. In a
retrospective review of 354 new molecular entities
available for evaluation that had been approved by
the US Food and Drug Administration (FDA)
between 1980 and 1999, 73 (21%) had had a
labelled dosage change; for 58 (79%) of the 73
medications, the change was a decrease in dosage.
The authors stated that “this pattern may represent
a systematic flaw in pre marketing dosage evalua-
tion; it has been common practice in the pharma-
ceutical industry to undertake phase III trials eval-
uating drug effectiveness at or near maximum-
tolerated doses.”3Perhaps more concerning is that
the need for dose adjustments has increased over
time: they were three times more common during
1995–1999 than during 1980–1984.3
At a minimum, a very low starting dose will
yield the potential benefits such as the placebo
effect and other nonspecific effects that are seen
in the placebo groups of clinical trials.4Recently,
a number of authors called for the return of place-
bos to clinical practice,5but this can be fraught
with a number of ethical dilemmas. Using a very
low dose provides a possible compromise in cap-
turing the placebo effect yet still providing a rea-
sonable therapeutic intervention.
Clinicians cannot reliably predict how any one
patient will respond to a drug (pharmacodynam-
ics). They can adjust for some of the pharmaco -
kinetic variability seen between patients by bas-
ing the dose of a medication on the patient’s
Is bigger better? An argument for very low starting doses
James P. McCormack PharmD, G. Michael Allan MD, Adil S. Virani PharmD
Competing interests:
Adil Virani receives
honoraria for educational
work done in conjunction
with or on behalf of the
Therapeutics Initiative. He
receives royalties in relation
to his role as lead editor for
the handbook Clinical
Handbook of Psychotropic
Drugs. No competing
interests declared by James
McCormack or Michael
Allan.
This article has been peer
reviewed.
Correspondence to:
Dr. James P. McCormack,
jmccorma@interchange
.ubc.ca
CMAJ 2011. DOI:10.1503
/cmaj.091481
Analysis
CMAJ
• The recommended starting doses for many medications are too high
for many patients.
• Unless the condition is severe or life-threatening, drug treatment can
be started at a very low dose (half or one-quarter the recommended
starting dose).
• Potential advantages of this approach include a further decrease in the
risk of adverse events, enhanced patient participation, improved
adherence and reduced long-term costs.
Key points
© 2011 Canadian Medical Association or its licensors CMAJ, January 11, 2011, 183(1) 65
big-mccormack_Layout 1 22/12/10 9:11 AM Page 65
weight and renal/hepatic function; however,
pharmacodynamic variability, which typically
exceeds pharmacokinetic variability,6is not really
taken into account by these adjustments.
In a meta-analysis of 39 prospective studies,
about three-quarters of reported side effects of
medications were dose related.7In a recent random-
ized controlled trial of colchicine, a dose of 1.8mg
was found to be as effective as 4.8 mg for the treat-
ment of acute gout; the incidence of diarrhea was
77% (19% severe) in the high-dose group and only
23% (0% severe) in the low-dose group.8
A cross-sectional study showed that patients
reduced their doses to reduce their costs.9As
clinicians, we have all had patients tell us they
have done the same to avoid side effects. They
take their medication every other day or take
half or sometimes even a quarter of the pill, and
they report that it works just fine. Many patients
are comfortable taking portions of tablets, and
these doses frequently strike the right balance of
benefit to cost and adverse events.
In animal research, in which breeding is
highly controlled to the point that the animals
are virtually genetically identical, there is still a
wide dose–response relation.10 In the less con-
trolled human environment, genetic and envi-
ronmental variability likely leads to an even
more varied dose–response effect.
Are initially marketed doses
too high?
When medications are first marketed, the recom-
mended starting doses are typically much higher
than those eventually found to be effective.
There appear to be a number of reasons for this
predicament.11 First, health protection agencies
require drug companies to show that a medica-
tion has an “effect” before it can be approved. In
general, the easiest way to show an effect is to
use doses that will generate a response in as
many patients as possible. These doses then
become the recommended dose. As Sheiner
states, “The dose studied is a dose almost guar-
anteed to be excessive.”12
A second reason is encompassed by the nat-
ural desire to have the medication work quickly
and completely. To ensure success of their prod-
uct, the manufacturer would prefer as many
patients as possible to have a clinical response on
first use. The clinician and patient are also keen
to see an immediate resolution of the clinical con-
cern. Although this approach has definite appeal,
it is not without potential complications. As noted
previously, about 16% of all new products will
have their doses officially decreased because of
safety issues.3Therefore, for one in every six new
medications, the initially recommended starting
dose is later found to be excessive and to have an
unfavourable risk–benefit profile. Even for med-
ications that do not require a later adjustment to
the labelled dosage, a number of patients would
benefit equally from a lower dose and a reduced
risk of adverse events. These patients may be
unnecessarily tolerating side effects or may stop a
medication that might otherwise have been help-
ful without adverse events at a lower dose.
A recent example shows how organizations
such as the FDA may play a role in advocating
doses that are higher than necessary. Varenicline
is a recently released drug for smoking cessation.
Based on two comparative dosing studies of
1 mg twice daily versus 0.5 mg twice daily, the
FDA stated that “varenicline 0.5 mg BID
appears to work as well as varenicline 1.0 mg
BID, so that subjects who cannot tolerate vareni-
cline 1.0 mg BID should take varenicline 0.5 mg
BID.”13 If 0.5 mg twice daily produces the same
effect as 1 mg twice daily, why is the lower dose
not recommended for all patients? The right dose
for a number of patients may be even lower, but
by advocating doses higher than necessary for
the majority of patients, the FDA has encouraged
physicians to start too high.
Evidence for effective lower doses
A number of randomized controlled trials have
examined the effect of lower doses (Table 1).8,14−25
Most of the studies showed no differences in
effect when half or one-quarter of the usual dose,
or even a smaller amount, was used. In the stud-
ies that showed a difference in response between
doses, the lower doses still typically produced a
clinically important response. However, these
studies did not look at the effect of doses lower
than those mentioned. In other words, these simi-
larly effective lower doses likely do not reflect
the lower part of the dose–response curve. Even
lower doses would probably have produced a
clinical response in a reasonable number of
patients. So, although evidence from randomized
controlled trials is helpful in showing that certain
low or very low doses work, this sort of evidence
is not definitively required to adopt an approach
of starting with very low doses.
Advantages of starting with very
low doses
One advantage is that patients would get the
potential placebo effect because they know they
are receiving something, albeit at a very low
Analysis
66 CMAJ, January 11, 2011, 183(1)
big-mccormack_Layout 1 22/12/10 9:11 AM Page 66
dose. This is all done without the need for
deception.
Another advantage is that patients would be
engaged in finding the best dose for them. Some
will appreciate the concept of “just a little bit to
start.” Although not specifically associated with
this approach to dosage, shared decision- making
has been associated with improved health-related
behaviours and clinical outcomes.26,27
In addition, cost savings would be consider-
able, as found in a retrospective review of phar-
macy claims.28 For example, the use of half a
tablet of a medication that normally would cost
$1/day amounts to more than $175 in cost sav-
ings per year. This savings would exceed the
cost associated with two or even three additional
office visits that may be needed to optimize the
target dose for a patient. Further cost savings
may be garnered because of improved clinical
outcomes owing to improved adherence to treat-
ment regimens that are better tolerated and
because of reduced adverse events.
Finally, most clinically relevant drug interac-
tions could be avoided. Even if a patient was
given a drug that led to a doubling of the concen-
tration of the drug started at a very low dose, by
using say a quarter of the normal starting dose,
the increased concentration would still be well
below that achieved with typical starting doses.
Limitations
The very-low-dose approach we propose does
not apply to acute life-threatening conditions or
when an immediate effect is desired (e.g., acute
alcohol withdrawal, moderate to severe pain
from osteoarthritis or reflux esophagitis, moder-
ate to severe asthma, angina, status epilepticus),
nor does it apply when the consequences of
underdosing are potentially dangerous (e.g.,
acute bacterial infections). In these cases, it is
better to err on the side of giving at least the rec-
ommended dosage immediately rather than using
a slow upward titration. In addition, the very-
low-dose approach (other than the initial titra-
tion) cannot be used in conditions for which a
therapeutic effect or outcome cannot easily be
determined (e.g., reduction in the frequency of
seizures in a patient who has seizures only once
or twice a year).
For some situations, such as the use of
angiotension- converting-enzyme (ACE) inhibitors
in patients with heart failure, guidelines recom-
mend starting treatment at target doses. However,
the main evidence showing a difference in out-
come between a high-dose and a low-dose ACE
inhibitor for heart failure came from a randomized
controlled trial in which the high dose was 7 to 14
times higher than the low-dose comparator.29
Although we are not recommending lower doses
as a target, this serves as an example of how some
dosing studies without mid-dose options create
uncertainty: Would half or one-quarter the high
dose be as effective as the high dose? We do not
know because these lower doses were not studied.
Regardless, there are potential advantages to start-
ing with a low dose and working upward from
there, to reduce the risk of side effects. In addi-
tion, if patients can tolerate half or one-quarter the
target dose, that is likely better than abandoning
the drug completely.
Undoubtedly some patients will end up
requiring higher doses. In these patients, the
strategy of starting with a very low dose could
result in some delay or inconvenience; this is a
counterbalance to the cost savings and reduced
risks of adverse events for all patients as well as
Analysis
CMAJ, January 11, 2011, 183(1) 67
Table 1: Examples of the effect of lower doses reported in randomized
controlled trials*
Medication
Lower dose
studied Result
Hydrochlorothiazide 6.25 mg/d Effective at lowering blood pressure;
first marketed at 50 to 200 mg/d14
Captopril 6.25 mg Effective at lowering blood pressure
as a single dose and when given twice
daily over a longer term; captopril
25 mg three times daily is still
commonly recommended as a starting
dose for hypertension15
Sildenafil 25 mg As effective as 50–100 mg for erectile
dysfunction16
Sumatriptan 25 mg Virtually as effective as 100 mg; most
drugs in this class have a flat dose–
response curve at the doses studied17
Fluoxetine 5 mg/d Effects at this dose were similar to
those at 20 mg/d and 40 mg/d18
Ezetimibe 0.25 mg 1/40th of the recommended starting
dose of 10 mg provided 50% of the
effect of lowering low-density
lipoprotein levels achieved with 10 mg19
Elemental iron 15 mg/d As effective as 50 mg and 150 mg for
treating anemia in elderly patients,
with fewer side effects20
Bupropion 150 mg/d Rate of smoking cessation at one year
was the same as that with 300 mg/d21
Atorvastatin 10 mg Produced two-thirds the effect on
cholesterol as that with 80 mg22
Ibuprofen 200 mg As effective as 400 mg for migraine
headache23
Ranitidine 25 mg As effective as 125 mg for heartburn
relief24,25
Colchicine 1.8 mg As effective as 4.8 mg for acute gout,
with fewer adverse events8
*The use of lower doses recommended for drugs that affect surrogate markers such as cholesterol
or blood pressure may not always translate into a decreased risk of cardiovascular events.
big-mccormack_Layout 1 22/12/10 9:11 AM Page 67
the clear advantage for patients requiring only
the lowest doses. A very-low-dose approach is
not meant to be dogmatic. Clinicians and pa -
tients should discuss the right starting dose
based on the patient’s individual characteristics
and history.
Starting with a very low dose may add some
complexity to treatment initiation and take more
time both in developing a treatment plan with the
patient and reaching the best dose for the patient.
During titration, some patients (and perhaps clini-
cians) may lose patience with the process and
assume the medication is ineffective after only a
few dose increases. Clinicians need to educate
patients about how the best dose for them may be
higher than the starting dose and that it may take
a few increases to find the right dose. For some
patients, our proposed strategy will take time,
particularly as titration plans are developed and
clarified, but we feel that the time will not exceed
that spent in normal, informed decision- making.
As well, time spent reaching the right dose may
result in increased adherence and may reduce the
time spent dealing with the consequences of too-
high doses or stopped medications.
Another limitation is that, although most side
effects are dose-related, some of the more seri-
ous life-threatening idiosyncratic allergic reac-
tions are often not dose-related and could still
occur despite starting with very low doses.
Finally, given that “side effects” are reported
in placebo groups of clinical trials, patients re -
ceiving very low starting doses may still report
side effects that may or may not be caused by
the drug.
Practical suggestions
A discussion with the patient about the ratio-
nale and approach to starting drug treatment at
a very low dose is essential. Clinicians should
explain how individuals respond differently to
different doses and determine whether the
patient prefers to start at a lower or higher dose,
after discussing the benefits and limits of each.
When starting with a very low dose, patients
should be advised that they may not respond
immediately and that, with upward titration, the
right dose that im proves the condition while
minimizing the risk of dose-related adverse
events will be found.
Not all drugs come in forms that allow small
doses to be used. However, the majority of
tablets can be split, especially with a pill cutter.
Although splitting tablets does not always result
in perfect sized pieces,30 patients need not be too
concerned if every piece is not exactly the same
size, even for drugs with a low therapeutic index.
Some capsules can be opened and the dose
reduced that way. Alternatively, the interval
between doses could be increased; for example, a
proton pump inhibitor could be taken every two
to three days instead of daily. Finally, a number
of drugs come in liquid form; for example, fluox-
etine is available as a liquid (20 mg per 5mL).
Conclusion
For most conditions that are not life-threatening
or severe, there are few legitimate reasons not to
start with a very low dose and titrate upward.
Dose titration will likely improve tolerability,
may improve adherence if side effects are re -
duced, and will reduce drug costs if a low or
very low dose is found to be effective. An alter-
native approach to determining the best dose for
a patient is to start with a higher dose, get a
response and then reduce the dose to the lowest
effective dose. Some patients may prefer this
approach, but it increases the risk of dose-related
side effects, and both the clinician and the pa -
tient may be reluctant to decrease the dose once
an effect has been achieved.
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Affiliations: From the Faculty of Pharmaceutical Sciences
(McCormack, Virani), University of British Columbia, Van-
couver BC; the Faculty of Medicine (Allan), University of
Alberta, and the Toward Optimized Practice program
(Allan), Edmonton, Alta.; and the Fraser Health Authority
(Virani), Surrey, BC
Contributors: All of the authors contributed substantially to
the conception and design of the article. James McCormack
drafted the article; all of the authors revised it critically for
important intellectual content and approved the final version.
Acknowledgement: The concept for this paper was inspired
by Dr. Robert Rangno, who regularly provided us with a
“high dose” of his clinical experience with very low doses.
Analysis
CMAJ, January 11, 2011, 183(1) 69
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