Hi Arnie,

You may know more about this than i do, but i have a couple of comments nonetheless.

First, it was not my idea to compare the incidence of PG (pathological gambling) among those on DAs to that of the general population - Both Drs. Stacy and Voon (the April 5th study) held up the indcidence and prevalence, respectively, in the general population for comparison. Stacy does not calculate signficance, but he does compare the two numbers - and derives meaning from the one being marginally higher than the other. Voon does the same.

Second, perhaps i misunderstand you, but it seems to me that you are saying two things.

first, it seems you are saying that statistical significance is insignificant in that it tells us nothing more than the degree to which certain results may or may not have been influenced by random fluctuations, and that tells us absolutely nothing of worth about the sources from which the raw data was drawn.

If i am understanding you correctly, then i have to ask why the calculation is undertaken as a matter of course in countless studies, and even more basic than that, why bother inventing (?) a calculation that merely give us a number - say, 42 -  from which we may derive no meaning whatsoever?

second, it seems to me you may be saying that beyond the uselessness of calculating significance itself, the two groups are not appropriate for comparison because, and please correct me if i have this wrong, PG among PWP is associated with the starting and stopping of DAs, and PG among the general population is not. could you clarify that for me?

because such comparisons are standard procedure  - take the question of suicide risk among cancer patients - “epidemiological studies have indicated that the risk of suicide in cancer patients is higher than that of the general population.” suicide is to the onset of cancer as gambling is to the onset of dopaminergic medication (in theory, at least)- and both suicide and gambling occur in the general population as well.  in what way is the comparison stacy and voon make different from cancer comparison?

and as far as the difficulty determining whether anyone has the behavior because of the tendency to lie about it - people lie about suicidal thoughts, about binge eating, about starving themselves, about pulling their hair out - people lie about lots of things and still studies are done, such obstacles and variables are taken into account and conclusions are drawn. this situation is no different.

regarding the statement that no study has shown an association btw gambling and levodopa monotherapy, i will actually put it in all caps - THE MOLINA STUDY found an incidence of 4-4.5% of PG among those on levodopa - no other drug is mentioned - just levodopa - and for some reason it is like that study is invisible.

anyone wants to read that study, i have it, happy to send it.

however, i totally agree with your assertion that whether or not it is a *real* effect is of tantamount importance, along with the mechanism of causation (is it mirapex, or DAs, or levodopa, or some combination thereof?) I also agree that the frequency of use of a particular drug must be taken into account when calculating the incidence of a certain behavior occuring on that drug vs other drugs of its kind.

but, i disagree that there is substantial evidence to support the existence of the association we are discussing - the Voon abstract *seems* to address some of the as yet unaddressed issues, but i am going to wait to read the full study before coming to any conclusions about that - and until then, the stacy, dodd and szarfman studies are all we have and they remain just as flimsy as they have been - in my opinion

anyway - if your takeaway were the final word and the goal of all of this sound and fury were to alert folks to this “danger,” i think it is VERY safe to say “mission accomplished.”

would it be nice if that were the final word? but it’s not - not by a long shot - this is going to spawn dozens of studies (time will tell if i am right) and syphon money away from research that could really help people - not to mention the danger of people being frightened away from DAs and into the arms of that most excellent drug, levodopa.

Arnie Kuzmack <[log in to unmask]> wrote: ----- Original Message -----
From: "mackenzie"
To:

Sent: Monday, April 03, 2006 3:04 AM
Subject: Re: DAs & Gambling: The Non-Story, Part III -
addendum II

[snip]

> I think I might hear a collective sigh of relief when I
> say that i think I am done debating this - will let you
> all know if there are any new developments.


As it happens, I have just gotten around to commenting on
this issue, so Mackenzie may not be able to keep this
promise.  (Not that the discussion has stopped in the last
few days anyway.)

The basic argument made by Mackenzie is that the rates of
pathological gambling reported in the various studies are
comparable to those observed in the general population, the
vast majority of whom do not have PD and are presumably not
being treated with dopamine agonists (DAs).  Certainly, the
rates for patients being treated with DAs in these studies
are not statistically significantly greater than rates in
the general population.

I will argue that this is not an appropriate comparison and
does not tell whether or not the purported effects are real.

Simplifying somewhat, tests of statistical significance for
occurrence rates (technically, prevalence) are used when
there are two population groups who may or may not differ on
some determinable characteristic.  Here, let's assume the
characteristic of interest is dichotomous -- you either have
it or you don't.  For example, we could be studying whether
members of two particular ethnic groups are more or less
likely to have completed a college degree.  The basic
procedure is to select random samples from each group and to
determine whether each of these individuals has completed a
college degree.  Now, since we have only a limited number of
people in each sample, the fraction with a college degree
will differ somewhat from what we would get if we had enough
money to ask every member of the two ethnic groups.
Further, it could happen that, just by chance, we happened
to get a few extra college grads from Group A and a few less
from Group B.  When we see a higher rate of college grads in
Group A than in Group B, we don't know whether it's due to
such a random fluctuation or whether there really is a
difference in the two populations.

A test of statistical significance will tell us whether the
difference in rates is so large that it is not likely to be
due to chance fluctuations.  If the difference is not
statistically significant, we don't know whether there
really is a difference or not -- we could select larger
samples from the two groups and maybe resolve the issue.
You can never prove that there is no difference, just that
it is too small to be detected in the sample sizes we have
available.  If there is a statistically significant
difference, all we know is that it is not likely to be due
random fluctuations in who we happened to get in our two
samples.  It does not mean that the difference is large
enough that we should care, and it does not tell us anything
about the reasons for the difference.

Now, back to the issue of DAs and pathological gambling by
Parkinson's patients.

The main problem with the statistical comparisons proposed
by Mackenzie is that we do not have two population groups
who may differ on some characteristic.  Rather, we have two
groups, people with Parkinson's and the general population,
who have two different characteristics.  The studies cited
have identified a number of people whose pathalogical
gambling behavior began after taking or increasing the
dosage of certain drugs and stopped when the drugs were
stopped or doses reduced.  In many cases, the gambling began
with a few months of treatment with DAs (although there are
some cases of longer periods), and it stopped typically
within a few months of stopping or reducing the drug
treatment.  By contrast, in the general populaton,
pathological gambling usually starts in adolescence or early
adulthood and builds up over many years until it reaches the
point of being "out of control".  There typically does not
seem to be any particular event that sets off the behavior,
and it continues until treatment is sought and is
successful.  Treatment is usually similar to that for
alcohol addiction.  Overcoming it is a very difficult
struggle.

Thus, it is of no particular interest whether the occurrence
rates of these two different behavior patterns in two
different populations are about the same or one is larger
than the other.  It *is* of interest whether this is a real
effect -- whether a few percent or so of patients treated
with DAs (and perhaps Mirapex in particular) will develop
pathological gambling behavior -- regardless of what people
do who do not have PD and are not taking dopaminergic drugs.

Of course, it is also of interest what the mechanism
of causation is and how it is related to the drug-treatment
regime and to characteristics of the patients.  For example,
does it really occur more frequently with treatment with
Mirapex, or do the apparently higher occurrence rates with
Mirapex reflect more widespread use of that drug?

In addition to the difference in the endpoints observed in
the PD/DA group and the general population, our situation
differs from the model of statistical significance in that
it is quite difficult to determine whether a particular
individual in either group has the behavior.  People with
pathological gambling behavior typically lie about it, and
it might require an in-depth relationship between the
investigator and the patient.  This would lead to
under-reporting of the number of cases; even worse, the
probability of missing cases of the behavior may be
different in the two groups.  In addition, as Mackenzie
points out, the publicity devoted to this issue could lead
to greater awareness of the problem and, hence, a jump in
the rate at which cases are detected.

Another uncertainty is the role, if any, of levodopa in
causing this behavior.  The recent studies do not seem to
have identified cases where patients who were treated with
l-dopa alone, without any DA, developed the gambling
behavior.  On the other hand, most of the cases identified
involved treatment with l-dopa *and* a DA; it is quite
possible that both play a role in development of the
gambling behavior.  As far as I know, nobody (except maybe
some lawyers) believes that a role for l-dopa has beeen
ruled out and that we can be sure that it's DAs alone (or
Mirapex in particular) that are the problem.  In fact, the
article posted on April 6 by Maryse seems to suggest that
the problem is more likely if the patient is taking both DAs
and l-dopa, but I have not seen the full report.

So where does this leave us?  I would suggest the following:

(1)  There is substantial evidence that the behavior pattern
we are discussing really does occur, though in a small
portion of patients, perhaps one percent to a few percent.
The evidence is less convincing than a randomized
double-blind trial but goes well beyond isolated anecdotal
reports.  The similarity of the pattern observed in these
studies -- pathological gambling within a few months of
starting on or increasing the dosage of DAs and a rapid end
to the bahavior when the drug is stopped or dosage
reduced -- lends credence to this conclusion.

(2)  Therefore, doctors, patients, and care givers should be
alert to the initial signs of pathological gambling or other
impulse-control problems and take appropriate action when
they occur.

(3)  It will be difficult to do a definitive study -- a
prospective randomized double-blind trial.  The subjects
would need to be informed about the purpose of the study,
which will influence their actions.  I would also question
whether it is ethical to withhold DAs from PWPs for long
periods.

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