While this thread started off as being about the DA drugs, I can see that there is a correlation to the way that we and/or our health providers are expected to perceive them, and L-dopa medications. So there seems to be a changing of boundaries that is lumping all dopamine replacement drugs together.

Alongside a major producer of sinemet reducing supply for large parts of the world through till 2011 it makes me wonder what other agendas there are....... Perhaps another big re-design for l-dopa......

Is this a subtle re-writing of PD that is expected to pass under the radar? I don't mean the study itself, but the addition of the DA warning to l-dopa preparations...

Judging from some descriptions of efforts to get off sinemet, they do not seem to differ that greatly from the description of the vulnerable group in this study. There was a study some years ago, perhaps around 2004, which made neuros nervous about the addictive potential of l-dopa, do not remember the detail, only the fall-out....... too off-topic..... as we will almost all be on l-dopa eventually, unless a cure comes along and surprises us, maybe it occupies a protected place among pd drug therapies, it would not do to have huge legal cases as in the case of Mirapex - hence we are all now warned...

It is good that someone has come forward and shown that these drugs affect patients in complex ways... I'm glad to hear of anything that brings more clarity.....

So there is a clear subgroup who are more affected, though a bigger study is needed, surely? It seems a very small group of individual patients affected, that makes a large percentage statistically, but may or may not be borne out in a larger cohort.

As these drugs affect us profoundly, it is more than the double standard, or one drug or the other - it is hard for patients to have any say in the way they are treated if they are mis-,dis- or simply not informed about their medications. I was not offered any information at all about medication - I was given sinemet, it worked and I was grateful, but I was wholly unaware of the implications of taking it, the potential for problems in the future until other patients educated me - time is teaching me why I should have been better informed right from day one, something I would wish for all patients.

It is good to see the breadth of thinking here...

Lindy

I find myself agreeing with everyone at some point. I have been the poster child for agonists and I think calling sinemet a "gold-standard" for anything is a joke. Initially it may work well for some, but I truly believe it causes far more problems than it fixes. Of course that is my experience and we know that it is irrelevent to any one else.

The thing I continue to find myself coming back to, time and again, is the realization of how very little the medical community actually knows, and how quick they are to go mucking about in our brains without, what I would consider, the requisite information.

what the prevalence of whatever impulse control disorders went into the 14% to 17% statistic is in the general population? Is not provided in the Eureka alert article.

Pam - once you are dx'd with PD you automatically become a human subject in the ongoing clinical trial that is Parkinson's disease. No matter how well informed we are as patients, and no matter how knowledgeable our physicians, our care is basically a daily crap shoot.

I'd rather the researchers spend their time trying to find out what the heck we're dealing with before developing more drugs to fix something they don't understand and that often prove to do more harm than good. Living long with PD is also new territory - we are all pioneers just by getting out of bed everyday.

I wonder if they have ever gone back to pre- agonist days, when sinemet was the only treatment, and explored whether that generation became compulsive? We live in a pretty impulsive, hyper society. Instant gratification. How much abnormality is necessary to be labeled compulsive......lol And who says so?

Workaholics are pretty driven.

paula

at least according to what I have found --

It always makes my antenna go up when a prevalence is cited, but compared to nothing -- i.e., 14 to 17% has no meaning as an indication of an association between dopamine agonists and ICD's unless it is compared to, and found to be significantly greater than, say, the prevalence of ICD's in the general population.

I bought the paper, and 14 to 17% represents the aggregated prevalences of pathological gambling, compulsive eating, hypersexuality, and compulsive shopping.

I went on to pubmed and noted down the prevalences in the general population for each of these disorders. I took the first prevalences I stumbled across.

The prevalences I found for these disorders in the general population add up to a range of 13.61% to 19.7%.

So according to what I have found 14% to 17% is not an elevated prevalence of these disorders -- it is the same as the general population.

If anyone is interested in the itemized statistics and sources, here they are:

pathological gambling
2.3% to 3.4%, (and possibly as high as 7% in certain geographical areas, but I did not use that in my cumulative total)
DSM-IV TR

compulsive sexual behavior
5% to 6%
CNS Spectr. 2006 Dec;11(12):944-55

compulsive shopping
5.8%
World Psychiatry. 2007 Feb;6(1):14-8

compulsive eating
0.51% to 4.5% depending on how you define compulsive eating
J Psychiatr Res. 2009 Sep;43(14):1125-32

you are right, this idea of levodopa safer than dopamine agonists in the context of impulsive behavior hasn't as far as I know been stated flat out, except by ambulance chaser law firms on the Internet.

However, there has been an incessant contrasting of dopamine agonists with levodopa in this context -- where levodopa is always presented as not causing these problems - even when, as is almost always the case, the person who has experienced ICDs is taking levodopa in addition to a dopamine agonist -- levodopa is always exonerated.

Forgive me if I've gone overboard, but here are probably far too many examples of what I'm talking about:

Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease
Stacy, et al. Neurology 2003

Quote from paper:
“No subjects on levodopa therapy alone or on any other DA-sparing regimen were found to have symptoms of obsessive or excessive gambling.”

Quotes from press coverage:
“All the patients were taking levodopa - which transforms into a crucial neurotransmitter called dopamine in the brain. But their new gambling habits appeared to be associated with another drug they were taking, a dopamine agonist. These activate the dopamine receptors in the brain.”

“None of the other patients taking ropinirole or only levodopa had a gambling problem.”

*****

Pathological gambling caused by drugs used to treat Parkinson’s disease
Dodd, et al, Archives of Neurology 2005

Quotes from paper:
“None developed new gambling or an increase in gambling while receiving levodopa monotherapy”

“Although levodopa therapy might have been a contributory factor [because everyone who gambled was taking it in addition to the dopamine agonist], none developed these problems when receiving levodopa monotherapy, and 3 patients had not been treated with levodopa. The relationship of pathological gambling to dopamine agonist therapy in these cases is striking”

“This article, as well as others from this systematic review, revealed that all patients [who gambled] were taking a dopamine agonist [and levodopa, but the authors leave that out of this sentence] but none were receiving levodopa monotherapy.”

Quotes from press coverage:
“Researchers noted that in seven patients, pathological gambling developed within one to three months of reaching the maintenance dose or with a dose escalation of the agonist; none developed pathological gambling while treated with carbidopa-levodopa alone.”

“They noted that in seven patients, pathological gambling developed within one to three months of reaching the maintenance dose or with dose escalation of dopamine agonist treatment; none developed pathological gambling while treated with carbidopa/levodopa alone.”

****

From the American Academy of neurologist press release for Voon study, 2006
“The researchers examined the medications patients were taking to see if these influenced risk for compulsive behavior. They found that almost all patients who developed these behaviors were receiving both levodopa and a dopamine agonist. Patients on levodopa alone were much less likely to develop a compulsive behavior.”

Other press coverage, same study:
“Parkinson's disease patients who gamble and take dopamine agonists to treat their symptoms are at higher risk for becoming compulsive gamblers, according to researchers from Canada. In a survey of over 180 patients, approximately 6 percent of those taking a dopamine agonist, either alone or in combination with levodopa (another symptomatic treatment), were compulsive gamblers, versus no patient on levodopa alone.”


****

Frequency of New-Onset Pathologic Compulsive Gambling or Hypersexuality After Drug Treatment of Idiopathic Parkinson Disease
Bostwick et al., mayo clinic proceedings 2009

Quote from paper:
“Among the study patients with PD, new-onset compulsive gambling or hypersexuality was documented in 7 (18.4%) of 38 patients taking therapeutic doses of dopamine agonists but was not found among untreated patients, those taking subtherapeutic agonist doses, or those taking carbidopa/levodopa alone.”

***

Long-term follow-up of impulse control disorders and Parkinson’s disease
Mamikonyan et al, Movement Disorders 2008

Quote from paper:
“For PD patients who develop an ICD in the context of DA treatment, discontinuing or significantly decreasing DA exposure, even when offset by an increase in levodopa treatment, is associated with remission of or significant reduction in ICD behaviors without worsening in motor symptoms.”

*****

Compulsive eating and weight gain related to dopamine agonist use
Nirenberg, et al., Movement Disorders 2005

Quote from paper:
“L-Dopa, for example, appears to be less likely to elicit certain types of compulsive behaviors—including compulsive eating—than dopamine agonists such as PPX [pramipexole].”

I've been waiting on-deck, but now would like to take a few swings at this lively, insightful, but somewhat confusing thread. And I will be speaking from my own experience, from the observation of others over a 16-year period (I believe that could equate to a longitudinal study lol), and from what I have read in the body of research. And I may sprinkle a little bit of opinion here and there, but for the most part my reply is what I consider to be "objective."

As I step up to bat, let's begin:

Swing 1: Assumed question: Do dopamine agonists contribute to ill side effects (e.g. compulsive/impulsive behaviors, changes in personality, etc. and/or hastening of symtoms) and are they a feasible choice for treating the symptoms of PD?

Answer: Yes and yes, but this is a qualified answer.

I will take a two-base hit, if you agree.

Discussion:
You have probably read the behavioral studies, but as of today the correlation has not been inconclusive. This lady doctor that indigogo introduced, however, has a differing opinion, and informationn that has formerly been clandestine.

Swing 2: Does levodopa (brand name - Sinemet)(or dopaminergic therapy) contribute to ill-side effects (dyskinesia, on/off phenomena, personality change, and/or hastening of the debilitating effects of Parkinson's disease) and is it an acceptable mode of therapy for PD?

Answer: Yes and yes, but again qualified.

I will take a one-base hit on this, if you agree.

Discussion:
I have consistently seen the dyskinesia rate increase with long-term treatment with levodopa. The dopamine agonists The on/off phenomena, however, I have seen in both those taking levodopa long-term AND those with the advancing of PD.

Swing 3: If these medications are known to cause debilitating (maybe even life-threatening side effects), why is the "bad" press/media focusing mostly on the dopamine agonists and not levodopa?

Answer: Before I answer, I have a question: Is anything fair in the world? (see discussion for the REAL answer)

Discussion:
bonan quoted:
". . . *in my opinion,* levodopa’s side effect profile is such that it could easily warrant as much bad press as dopamine agonists are getting – but it gets none." (edited)

Yes, that could be true of most all of the neurological drugs. With carbidopa/levodopa therapy the results are DRAMATIC. I would compare it with deep brain stimulation as far as the impact of its results. And it has had its share of bad press over the 40+ years since its discovery. There is rapid dose titration (unlike the agonists, which must be titrated either when starting or ending usage), and it has been around so long that it is very inexpensive. (Have you priced the extended release DA's?)

The occurrence of involuntary movements may require dosage reduction.
Blepharospasm (a mini spasm of the eyelid) may be a useful early sign of excess dosage in some patients.

Not to compare, but just so you know the side effects of DA's:
WARNINGS), bradykinetic episodes ("on-off" phenomenon), confusion, agitation, dizziness, somnolence, dream abnormalities including nightmares, insomnia, paresthesia, headache, depression with or without development of suicidal tendencies, dementia, pathological gambling, increased libido including hypersexuality, impulse control symptoms.
rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants.
Source Rxlist.com:

To begin with, we should make ourselves very familiar with the history of levodopa. The following has been paraphrased by moi, the source being:
NEUROLOGY 1998;50:S2-S10
© 1998 American Academy of Neurology

History of levodopa and dopamine agonists in Parkinson's disease treatment.

* 1960-The discovery of striatal dopamine deficiency in Parkinson's disease * This was a key event that led to the era of levodopa therapy.
* 1961- Levodopa was first tried in PD patients, but throughout most of the * * 1960s the results were inconsistent.
* 1967 -Cotzias and colleagues reported dramatic improvement in PD patients with oral administration of levodopa in increasing amounts over long periods. As the drug was increased, however, the major side effects of levodopa also became apparent. Dyskinesias and motor fluctuations, also became apparent at this time.
* 1970's- (early)the advantages of adding a dopa decarboxylase inhibitor to treatment were discovered-reducing side effects and gaining better symptom control.
*1975- the first levodopa combination, carbidopa/levodopa, became commercially available.

Since then, PD researchers have attempted to overcome complications with such techniques as continuous levodopa infusion and, most recently, long-acting levodopa combinations.

1970 -A dopamine agonist, apomorphine, was used as a means to overcome side effects and loss of levodopa efficacy. However, side effects and difficulty of administration limited its use. (Note: this treatment has more recently been introduced as "New" therapy, namely - Apokyn - which is administered as an injectionfor a quick fix with the on/off phenomena. However, today I don't believe it is breaking many sales records.)

1974 -Dopamine agonists began to find a place in routine treatment of PD bromocriptine's benefits in PD.** see note below

Since then, new approaches have been tried, such as dopamine agonist as monotherapy (meaning that's the only med you take for a specific disease)and early adjunct therapy in combination with levodopa. For some reason that I could not conclude, the aging patient cannot tolerate the DA's as well as younger patients, so those thinking they will never take levadopa may have to rethink that position.

The development of new dopamine agonists led to dopamine receptor subtypes and agonists targeted to stimulate specific receptors.

** Bromocriptine is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (Hmmmmm - here's a close association with PD and diabetes.)

Home Run! Now to complete my little analogy,see if you agree.

Conclusion
Sinemet (carbidopa/levodopa )simply works.
For the record about 95% of an oral dose of levodopa is metabolized outside the brain due to the blood brain barrier. I'm impressed that it works at all! But I see the dramatic results in myself (I have been taking it for 16 years now), and I've monitored it about 20 years in others.

I have had several close relationships with people with advancing Parkinson's. Some have been elderly, some not. The end result is the same. You become a prisoner in your own body, but your quality of life until that time depends on your personal choice of therapy. I had a big name researcher to tell me that he believed Sinemet was neuroprotective, because prior to its discovery being diagnosed with PD was a death sentence (5-10 years life expectancy). PD is a life sentence - you must manage it from diagnosis until death. PD cannot be ignored. I choose to live my best quality of life now, any way I can get it - in huge successes of treatment or in small victories.

If you agree that's fine. If not, that's OK, too. Either way I hope you have learned something from all this.

Peggy

Bingo. Given the current limitations in our research model-mainly that patients aren't generally listened to or have direct influence in driving the direction of pharma research, this is the best we can expect. We're a living laboratory and possibly hold answers, no, in fact we do hold answers. Only no one is bothering to really record or even take notice when things go awry, that's why this type of study is important. Until we see research like this....

I don't think it should end up with us passing judgment on one another or casting aspersions at whether we already have gambling tendencies or what not. We're all in this leaky boat together.

As someone relatively new to a diagnosis, I can say there seems to be a lot of myth generated around these drugs...Mirapex ruined/saved my life, and Sinemet stops working. Agonists are hell for some, and actually Sinemet continues to work but as disease progresses we need higher doses to provide relief. Whenever I read that it only works 3-5 years, I want to scream. Tell that to members here, like Fiona or Robert, who use it successfully much longer. The agonists don't work forever either. The point is that neither drug is ideal because they mask only and may cause harm that is more detrimental to us than freezing or shaking...

What doesn't help is the dogma that takes hold in clinical practice that then gets passed onto patients as "THE way to treat". It even seeps its way into our forum here, and we're pretty informed. I read too many upsetting posts by bewildered newbies who are maxed out and whacked out on agonists because their neuro says no Sinemet? A current look at the revised AAN's guide to treating PD will show you that there is really no need to withhold levodopa therapy and that clinically whether you start on agonist or with levodopa, we all tend to even out in around 6-8 years. Boann is doing exceptionally well. Like Fiona, I was started on Sinemet almost immediately. In my mind, why would I want to take max dosage to get partial symptomatic relief, when I can get full control of my tremor with a low dose of our gold standard?

<Boann, I'm curious as to how the side effects between Sinemet and Mirapex differ so greatly? I thought nausea and drowsiness were the main ones shared. I; however, was more put off by the signs in my neuro's office to call immediately if I experienced any sort of compulsive behavior while taking an agonist. Whereas with Sinemet, I may experience darkening urine-well okay, I can handle that. I have found Sinemet to be a pretty easy going drug for a neuroleptic. I end up naming all my pills and have dubbed it "Mellow Yellow".>

Who knows what any of these drugs do to us long term? Frankly, I'm at the point where I don't much care anymore; they are woefully inadequate, I'd much rather they research what in the heck we're ingesting, breathing, or drinking long term that gives us PD in the first place.

Laura

I failed to answer your question concerning my alluding to the fact that DA's are neuroprotective.

Over the years in both the education field and pharmaceutical research world this same adage applies, WHAT GOES AROUND COMES AROUND.

Some examples in education are given:
One year you may be mandated to teach reading "whole language," throwing phonics out the door. Students were taught to use contextual cues (guessing wh at makes sense to fill in the blank word), much was based on memorpzing "sight words," and teachers were to accept spelling by sound (callediinventivee spellingn). I went back to collegel and graduated at age 34. In a required class called "Linguistics," kids were dropping like flies because they had not had phonics (learning to attack a word by sound). I aced it because I was taught to attack words phonetically..

Again this happened with the metric system. Somebody decided that since we were the only country who did NOT use metrics, that that would be taught in schools throwing away our mode of measurement - it failed miserably.

My point is I may read a study one day that says "dopamine agonists are neuroprotective," and two years later that same study may be misproven. I am beginning to think that ANY study can be found to be flawed - some more obvious than others.

Fiona, I am hanging onto the hope that those early studies about DA's and selegeline/Eldepryl ARE neuroprotective, so I continue to take them.

And about that Azilect study, I don't think a year, even 2 or 3 is long enough to constitute a longitudinal study. Let's look at 8-10 plus for some really practical results.

Peg