Gambling & Parkinson's Meds – Just Read the Studies, OK? They Are Short!

This is the first in a series of articles - not sure how many just yet, but at least four, and probably five - in which I am going to put out there, finally, everything I have learned about the gambling claim. The first article is meant to illustrate why I think the claim is disturbing, in the second, third and fourth, I will take the three most publicized studies apart, one at a time, and in the fifth, I will document the reactions I have received from various parties in my quest for answers and honesty.

BACKGROUND
If you have Parkinson’s--and quite possibly even if you don’t--chances are you have seen at least one headline since August of 2003 purporting an association, and even a causal association (there is a distinction) between a certain type of Parkinson’s medication and pathological gambling (PG).

Since then, one hears – rarely firsthand, in my case, and usually not even firsthand for whomever one is talking to – horror stories of people losing their jobs, houses, spouses, children, everything, because they started to gamble uncontrollably while on this type of Parkinson’s medication. The primary “evidence” of an association is a loose (so loose as to be undefined, in some cases) temporal relationship between the start/cessation of the drug and the onset/cessation of the behavior.

The medications in question are known as dopamine agonists (DAs), and they function by stimulating the reaction on the part of dopamine receptors that dopamine would if it were present in the appropriate quantity – which it isn’t in the case of Parkinson’s disease (PD). The dearth of dopamine, which is crucial to the facilitation of normal movement, results in three cardinal symptoms: tremor, bradykinesia (slowness of movement) and rigidity (involuntary, immobilizing clenching of the muscles).

DAs have been around for years and years, but several new ones hit the market in the late ‘90s and one in particular, pramipexole, is giving the ol’ standard for treating Parkinson’s, levodopa, a run for its money. Levodopa differs from DAs in several ways, one of which being that it is metabolized into actual dopamine in the brain. It has been the mainstay of Parkinson’s treatment since its introduction in 1970. The makers of pramipexole, Boehringer Ingelheim, say in their 2005 Annual Report (1) that their DA has garnered 20% of the Parkinson’s pharmacotherapy market – before pramipexole’s introduction in 1997, most of that 20% belonged to levodopa products. In a broader context, a November 2006 presentation put together by Orion (makers of the most recent iteration of levodopa, Stalevo), has DAs overall dominating the Parkinson’s pharmacotherapy market with 48% of market share. (2)

DISTURBING BECAUSE…
When I first read about the gambling claim, I was disturbed for two reasons. First, because for many people, DAs provide a grace period of indefinite length before they may have to start taking the mainstay of Parkinson’s therapy, levodopa, which is crucial, given levodopa’s side effects. Second, because I knew that compulsive behavior could occur while one was taking a DA but be completely unrelated to it.

WHEN THE “GOLD STANDARD” FOR TREATING YOUR DISEASE IS SAID TO HAVE A HONEYMOON PERIOD, YOU KNOW YOU ARE IN TROUBLE
Levodopa works for varying periods of time for each person – the younger one is, the shorter the “honeymoon period” is likely to be. The fact that the term “honeymoon period” is employed at all, in reference to the period of time during which the drug actually works should be a giant red flag to anyone considering taking it.

Once the honeymoon period is over, which is within five years for about 80% (3) of those who take it (most people live with Parkinson’s for at least fifteen years) (4) , the efficacy of levodopa begins to deteriorate, a phenomenon euphemistically referred to as end-of-dose “wearing off.” There are various strategies for trying to manage these deficiencies, which ultimately leave most people with PD tied to a complex cocktail of medications (upwards of 20 pills per day) that must be taken on a meticulously timed schedule– all of which might not be so bad if these drastic measures actually worked, but they don’t.

The length of efficacy of each dose continues to decrease, leaving people immobile with rigidity at inopportune moments. People also start experiencing mid-dose failures of the medication (known as “on-off fluctuations”). These are even more unpredictable, and therefore dangerous, than the end-of-dose wearing off is. And when I say dangerous, I mean like falling down in one’s house and not being able to get up – which, if one lived alone, would be a problem. Keep in mind that one’s inability to move will not just go away by itself – one would be stuck there until someone happened to come along. And, for the piece de resistance, when people are experiencing the most benefit from levodopa, i.e., their ability to move is at its peak, they also experience dyskinesias (5) , which are uncontrollable, involuntary muscle movements, which, as you might imagine, interfere with the benefit one is gaining from being able to move.

I do not have dyskinesias myself, but have come into contact with quite a few people who do. For example, I spoke to one woman on the phone who said she was lying on the floor because her bodily movements were so violent that she could neither stand nor sit; I could barely hear her over the noise of the handset being knocked around.

Once this side effect manifests, it only gets worse. There are myriad drugs, known collectively as levodopa adjuncts, prescribed in the name of ameliorating all of these debilitating side effects, but none of them really works. Once the honeymoon period is over, it is straight downhill, at one speed or another, to brain surgery – the ultimate levodopa adjunct.

DOPAMINE AGONISTS – NO HONEYMOON PERIOD
My own experience has shown me that DAs can be effective indefinitely, without any of the side effects that come with levodopa. I have been on one for six years, and while it is not as effective as it once was, I do not have dyskinesias, I do not experience end-of-dose wearing off or mid-dose failures – and I have had symptoms for 10 years.

As far as randomized, controlled, clinical trials go, a study published in 2004 had the following to say:

“Our findings show that after 4 years of treatment, 74% of subjects assigned to initial levodopa experienced a dopaminergic motor complication (wearing off, dyskinesia, or on-off fluctuations) compared with 52% of subjects assigned to initial pramipexole. The treatment differential was most striking for dyskinesias (54% of subjects in the levodopa group vs 25% of subjects in the pramipexole group) and wearing off (63% vs 47%, respectively)” (6)

A little tidbit that is left out of the above is that subjects were permitted to take supplemental levodopa, if “necessary,” even if they were in the pramipexole arm of the study, which means that when one looks at those numbers, one should be aware that out of 151 subjects in the pramipexole arm, only 42 were not also on levodopa, so the numbers above are skewed to some unknown degree – in other words, the incidence of dyskinesias and wearing off would have been even lower, possibly significantly lower, in the pramipexole arm if the participants had not also been on levodopa.

However, the same study found levodopa to be more effective symptomatically than pramipexole. Each treatment arm experienced an initial improvement. However, the initial improvement was greater in the levodopa arm, so, since the subsequent decline in both groups occurred at about the same rate, the gap between the two arms remained constant. By the 48-month mark, the total UPDRS (Universal Parkinson’s Disease Rating Scale) score in the pramipexole arm had deteriorated 3.2 points past baseline, while the levodopa arm had only deteriorated to two points above baseline. In other words, at four years, the folks on pramipexole were slightly more, and the folks on levodopa slightly less, debilitated than they had been at the start.

And again, the flip side of the fact that the pramipexole arm was allowed to take levodopa would seem to indicate that the pramipexole arm might have deteriorated more had 2/3 of it not also been taking levodopa.

However, a second study published in 2006 analyzed the same data as above from the perspective of HRQOL (health-related quality of life) and found the following:

“In summary, subjects randomized to initial pramipexole compared with initial levodopa in early PD showed distinct HRQOL profiles over time. The HRQOL gains associated with pramipexole become more apparent in years 3 and 4 after initiation of the therapy. That certainly raises the possibility that a longer-term study would show even larger gains.” (7)

Moreover, side effects that were more severe in the pramipexole arm in the 2004 analysis, including freezing, somnolence and peripheral edema (swelling of the feet and ankles), were found not to have significant negative effects on HRQOL in the 2006 analysis.

COMPULSIVE BEHAVIOR CAN OCCUR WHILE ON A DA BUT BE UNRELATED
It also disturbed me because I knew that one could engage in compulsive behavior that was completely unrelated to the DA one was on, because it happened to me. For part of the six years I have been taking a DA, I got a little too much pleasure out of shopping – but it could not have been classified as a side effect of the drug by any of the standards of measure used by any of the studies I plan to dissect. I was depressed (due to circumstances in my life for the most part unrelated to Parkinson’s) plain and simple, and that is what the onset and resolution of the behavior corresponded with, temporally speaking – it did not correspond with initiation of the drug or any dosage change (there has been no dosage change in almost six years).

So, I started reading studies.

But before I go on, I want to be very clear that I am not advocating the taking of pramipexole over the taking of levodopa even if with pramipexole one experiences adverse events that one considers intolerable. I am advocating being fully informed when making decisions about one’s therapy. I am advocating actually reading the studies themselves, because what gets published and publicized is mind boggling. I am advocating that people not eliminate pramipexole as an option without even trying it, based solely on this sort of publicity. But I would never advocate that anyone continue to take something they feel is not good for them.

I hope to put the next installment, which is awaiting the attention of my editor friend, up soon. In it, I take a very close look at the study that started this wave of publicity.

*****

(1) Boehringer Ingelheim’s 2005 Annual Report

(2) Orion in the Parkinson’s Disease Market, November 2004 (link will download pdf)

(3) Medical Crossfire, Continuing Medical Education, Spotlight on Parkinson’s, June 2005 (link will download pdf)

(4) Estimates of average age at diagnosis differ but most hover just below 60, and life expectancy in the US is 77.9 years (Centers for Disease Control)

(5) Shaw KM, Shaw AJ, Stern GM. The Impact of Treatment with Levodopa on Parkinson's Disease. Quarterly Journal of Medicine, New Series XLIX, No. 195, pp. 283-293, Summer 1980

(6) Parkinson’s Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol. 2004 Jul;61(7):1044-53.

(7) Noyes K, Dick AW, Holloway RG; Parkinson Study Group. Pramipexole versus levodopa in patients with early Parkinson's disease: effect on generic and disease-specific quality of life.Value Health. 2006 Jan-Feb;9(1):28-38.