E-drug: Dose discrepancies between a reference book and medical
literature (cont)
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Dear E-druggers,
Dr Cohen's writings have omitted a crucial point: the Physicians' Desk
Reference (PDR) is merely a compilation of the subset of officially
approved labeling for each pharmaceutical product registered in the USA
that happen to be included in the PDR. The PDR has no editorial
responsibility for the text, other than to assure that official labeling
is accurately reproduced. Not every registered pharmaceutical product
is included in the PDR, because the PDR is a commercial venture that
provides space for official labeling of those products whose
manufacturers find it cost-effective to pay for the space. If there is
evidence that the recommended doses are suboptimal, the responsible
parties are the drug's manufacturer and the FDA, which jointly agree on
product labeling, which includes the recommended dosing regimen.
That some recommended doses are suboptimal is not exceptional, as Cross,
Peck and colleagues reported in a poster at this year's American Society
for Clinical Pharmacology & Therapeutics meeting, and as one can infer
from looking at changes in defined daily doses that have occurred in the
past 2 decades, compiled by the WHO . WHO Collaborating Centre for Drug
Statistics and Methodology in Oslo and posted on their website.
Dr Cohen asserts that higher-than-necessary doses are responsible for
patient noncompliance. That statement is a reiteration of one of the
many myths about patient compliance that have been dispelled in the past
decade by reliable measurements. The myth is that noncompliance is
'caused' by this, that, and the other aspect of individual
pharmaceuticals -- side-effects, inconvenient regimens, disappointing
response to the drug, early good response to the drug, etc. etc., not to
mention drug non-specific factors, such as poor doctor-patient
communication, lack of patient education, and so forth. Discrediting
of these oft-repeated 'reasons' for poor compliance is a key finding
from the past decade of research with electronic monitoring methods,
which, together with the low-dose phenobarbital marker, are the only
reliable methods for measuring compliance. Electronic monitoring is
the only method which shows dose timing, day by day, thus providing a
very useful tool for measurement-guided medication management, to
improve poor compliance.
The research findings, which one can find compiled in the bibliography
of over 500 publications based on the use of electronic monitoring, at
www.aardex.ch, are that the patterns of good, partial, poor, and total
non-compliance are remarkably similar from drug to drug, disease to
disease, irrespective of prognosis or symptoms. Another surprise, which
is still more anecdotal than formally studied, is that the compliance
patterns of health professionals -- pharmacists, nurses, doctors,
and, in particular doctors who self-prescribe -- are not notably
different from those of patients who have no specialized training or
education in health-related matters.
This finding, which needs to be confirmed in more formal studies, casts
grave doubt on the oft-asserted value of 'patient education' as a
solution to 'the compliance problem'.
Meanwhile, it is useful to define terms. 'Patient compliance', which
means 'the patient's compliance with the prescribed drug regimen', is
defined as 'the extent to which the patient's actual dosing history
corresponds to the prescribed drug regimen', and thus is synonymous with
'the quality of the patient's execution of the prescribed drug
regimen'. (Some prefer to call this 'adherence', but see below.) Early
discontinuation of treatment is quite another phenomenon, clearly
important, both therapeutically and economically, but inherently
dichotomous, while 'compliance', as defined, is a continuous
variable, capable of fluctuating from day to day, week to week, month
to month, as long as the patient continues with the drug regimen.
Thus, it is useful to define several additional terms: patient
'adherence', which is an overall, qualitative term, without specified
physical dimensions, subsumes 'acceptance' of the drug regimen,
'execution' of the drug regimen, and 'discontinuation' of the drug
regimen, and can refer (necessarily vaguely) to any one of the three,
or all 3. The length of time that a patient persists with the drug
regimen (whether well or poorly executed) is usually called
'persistence'.
What Dr Cohen is referring to, as a consequence of untoward
side-effects, is poor persistence. Patients who find that a particular
regimen of drug administration causes them distress respond mainly by
discontinuing the regimen, once and for all, sooner or later -- usually
sooner in the case of drugs that have a high incidence of untoward
effects. There are very few drugs whose pharmacodynamics are such as
to
cause patients to debate, dose by dose, whether they want to take the
next dose or not. Furosemide happens to be one, because of the
immediately copious flow of urine that it triggers, and which
persists for several hours -- not really a side-effect, because it is
the drug's primary action, but nevertheless often inconvenient
because it forces the patient to be close to a toilet for several
hours following the daily dose. That set of
dynamics leads many patients to defer the daily dose from a usual dosing
time, e.g., first thing in the morning, until later in the day, after errands
have been run, etc. Another drug with a closely dose-related
side-effect is cholestyramine, which has dose-dependent colonic gas
generation -- sometimes an unwanted effect, and one that leads
patients to curtail dosing prior to a social situation in which
copious gas generation would be difficult to contend with. That
effect can be seen in the papers describing the Lipid Research
Clinics - Coronary Primary Prevention Trial, published in JAMA back
in 1984, which show that measured compliance with the cholestyramine
was displaced downwards by about 20% relative to measured compliance
with the placebo. (The meaning of this effect has been much
misinterpreted by many well-meaning noncombatants who never
themselves took the drug, and so have over-intellectualized the
observed effect.)
But these two examples, furosemide and cholestyramine, are rarities.
Most drugs with unpleasant side-effects have them in a manner that is
not immediately temporally linked to the last-taken dose, but
gradually come on, like the fog rolling slowly into San Francisco,
through the Golden Gate. As a result, patients prescribed such drugs
usually soldier on, for a time,
until their patience is exhausted and they discontinue the medicine. It
is, of course, now possible to study these dynamics with electronic
monitoring, so that one can see the day-by-day dosing patterns, and,
where appropriate, interrogate patients from time to time about how they
happen to feel just then. My colleague, Dr Erik de Klerk, is presently
writing a thesis in the Department of Rheumatology at Maastricht
University on just such observations in patients with various rheumatic
conditions prescribed various anti-rheumatic drugs.
As for persistence, it is lamentably poor, even with drugs that have
side-effect profiles hardly different from that of the placebos against
which they were tested in pivotal, premarket trials, e.g., the statins
and the latest generation of antihypertensive agents. That is not to
say that these drugs have "no side-effects" (except in the scientific
sense) because the incidence of various unpleasant sensations is
certainly not zero among recipients of placebos in various medical
conditions that are generally considered to be asymptomatic, e.g.,
mild-moderate hypertension, hyperlipidemias, type II diabetes
mellitus, early osteoporosis (excepting the peri-menopausal symptoms
of 'hot flashes' and other manifestations of acute estrogen
deficiency. These 'nonspecificside-effects are easily and probably
frequently attributed by drug recipients to the drug, and can of
course be a trigger for early discontinuation, even though the
attribution may be wrong.
Three good papers to read on the subject of poor persistence with
nominally side-effect-free drugs in asymptomatic conditions are:
Jones JK, Gorkin L, Lian JF, Staffa JA, Fletcher AP. Discontinuation
of and changes in treatment after start of new courses of
antihypertensive drugs: a study of a United Kingdom population. BMJ
311: 293-5, 1995.
Caro JJ, Salas M et al. Persistence with treatment for hypertension in
actual practice. Canad Med Assoc J 1999;160:31-8
Caro JJ, Speckman JL et al. Effect of initial drug choice on
persistence with antihypertensive ttherapy: the importance of actual
practice data. Canad Med Assoc J 1999;160:41-7
Note that all 3 studies were performed in Canada or the UK, where
prescription drugs are substantially reimbursed, making it difficult to
argue that these early discontinuations were economically motivated.
Those who are interested in improving the quality of ambulatory
pharmacotherapy have their work cut out for them in the more or less
loosely coupled problems of poor compliance and poor persistence with
prescribed drug regimens.
John Urquhart, MD, FRCP(Edin)
Professor of Pharmaco-epidemiology, Maastricht University, Maastricht,
NL
Chief Scientist, AARDEX Ltd/APREX Corp, Zug, CH & Union City, CA, USA
Professor of Biopharmaceutical Sciences, UCSF, San Francisco
home office: 975 Hamilton Ave, Palo Alto,CA 94301 USA
email: urquhart@ix.netcom.com
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