Study Finds No Evidence of Increased Prevalence of Pathological Gambling Among Those with Parkinson's Disease

The first study I know of that actually compared the prevalence of pathological gambling among people with Parkinson's disease with the prevalence of pathological gambling among people without Parkinson's disease found no evidence to support an elevated prevalence among people with Parkinson's disease. The study, entitled "Hypersexuality and pathological gambling in Parkinson's disease: A cross-sectional case–control study," was sponsored by a Hospital Program for Clinical Research (local funding), Clermont-Ferrand University Hospital, Clermont-Ferrand, France and published in the well respected journal, Movement Disorders, in 2011.

Quoting from the abstract:

BACKGROUND:
Substance and behavioral addictions have already been described separately or in combination in Parkinson's disease. However, no comparisons of the prevalence of addictive behaviors in patients with Parkinson's disease and the general population have been published. The objective of this study was to compare the prevalence and characteristics of addictions (gambling, hypersexuality, tobacco, and alcohol) in patients with Parkinson's disease and in a matched, paired sample from the general population.

METHODS:
After matching for age, sex, and complete field questionnaires on addictions, we had 115 data sets.

RESULTS:
No difference was observed between Parkinson's disease and control populations concerning pathological gambling (0.87% vs 0.87%, P = .99), tobacco addiction (1.7% vs 1.7%, P = .99), and alcohol dependence (2.6% vs 3.5%, P = .71). The Parkinson's disease group showed 2 cases of sexual addiction (1.7% vs 0, P = .15).

CONCLUSIONS:
Our results indicate that patients with Parkinson's disease do not have specific profiles for tobacco or alcohol addiction and pathological gambling compared with the general population.

To the law firm that comes to my blog periodically, I hope you find this interesting. And if you didn't already know about it, I truly hope you find it helpful in your work.

If there Really is a Possible Association between Sinemet & Gambling, Why Is It not Being Publicized?

Further detail on the question of why this is not being publicized if it's true, given that the FDA clearly knows about it...

In early 2006 a research letter to the editor*, which is not peer-reviewed, was published and publicized across the Internet. This letter was written in support of a 2005 paper claiming to have found an association between dopamine agonists and gambling based on the fact that 11 people gambled while taking dopamine agonists.

The authors of this 2006 research letter had mined the FDA's adverse event reporting system database looking for correlations between gambling reports and drugs. The adverse event reporting system is a database of reports of adverse drug events.

The authors say they found exorbitantly high correlation between reports of gambling and mirapex. They did not find a correlation between gambling and any other drugs, including levodopa.

What the authors of the study did not reveal was that of the 39 reports linking gambling and mirapex, 38 of those reports came in after the publication and plastering across the Internet of the first gambling study in 2003.

That means that in the first six years mirapex was on the market, there was only one report linking it to gambling -- 38 came in after the first study was published. Given that huge differential between before and after publicity, and given that virtually no reports came in before the publicity, there is a distinct possibility that these reports at least some of them were generated by the publicity. And when I say generated, I mean that people who would have gambled anyway with or without an agonist might have erroneously attributed to gambling to the drug.

For example, I guarantee you that if someone published a study saying that tetracycline makes you giggle, there would be a deluge of reports linking tetracycline and giggling -- and even if tetracycline did make you giggle really, some of those people would have giggled anyway with or without tetracycline. Not taking this into account would result in artificially high correlation between tetracycline and giggling.

The likelihood that publicity had an effect on the reporting rate was not addressed in a research letter in spite of the fact that one of the authors cautioned her audience against overlooking the possibility of such an effect in a presentation I found on the Internet.

Instead, the data was presented as if it incontrovertibly confirmed an association between the drug and gambling.

Three of the authors worked at the FDA. There was a disclaimer at the end of the research letter saying that these opinions were not necessarily those of the FDA, but nonetheless, the authors were openly associated with the FDA in press coverage of the research letter findings.

Just to call out the most interesting points here -- FDA employees mined the adverse event reporting system database and DID NOT find an association between levodopa and gambling.

FDA employees published a study that fanned the flames of the idea that mirapex and gambling were associated and cautioned people to be on the alert for such phenomenon.

Fast forward to end of 2008 -- the exact same paragraph word for word that has been in the mirapex label for a couple of years now is inserted into the Sinemet label under the FDA's watch and approval, and not a peep -- not a word to the public - all those hundreds of thousands of people who are taking Sinemet who don't know that the FDA now says that the drug they are taking might be associated with pathological gambling.

If it's true, why have FDA employees not published it across the Internet, like they did in 2006 with Mirapex? If it's not true, why did Bristol Myers Squibb/Merck put it in its label, given that it is not coming under any fire whatsoever for an association between Sinemet and gambling?

*“Association Between Pathologic Gambling and Parkinsonian Therapy as Detected in the Food and Drug Administration Adverse Event Database” by Ana Szarfman, MD, PhD, P. Murali Doraiswamy, MD, Joseph M. Tonning, MD, MPH, and Jonathan G. Levine, PhD published in the Archives of Neurology in February of 2006.

Sinemet (Levodopa) & Gambling! Who Knew?

Only those who read product labels, because this definitely hasn't been publicized.

I was just perusing the most recent (12/2008) Sinemet product insert and i found the following paragraph:

"There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges, and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease, including SINEMET. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with SINEMET. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges, or other intense urges while taking SINEMET. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking SINEMET."

The fact that (ballparking) 95% of all cases of gambling that have been blamed on dopamine agonists were also taking levodopa has been consistently disregarded by study authors and not even mentioned in news articles.

AND anyone who has taken the fact that Boehringer Ingelheim, which has come under relentless fire for Mirapex, voluntarily (I believe) put a similar warning on their label a couple of years ago as an admission of guilt must now ask themselves why Merck/Bristol Myers Squibb would do the same, if it was voluntary, or why they would be required to, if it was not (I haven't been able to determine which it was) when they have come under no fire at all.

I would also ask why this hasn't been publicized - *vastly* more people are taking levodopa than are taking dopamine agonists.

Actually, I don’t think there is enough evidence to support either drug, taken as prescribed, causing such behavior – however, if dopamine replacement therapy must be blamed, then they both must be considered possible culprits – reports linking levodopa to hypersexuality, for example, far pre-date the approval of Mirapex.

It looks like they also added language about melanoma...

I haven't seen that in the news, either - has anyone else?

Most disturbing to me is that, if there really is a possible association between Sinemet and gambling, this supports my position that dopamine agonists have been being unfairly maligned.

Questions Regarding Mayo Clinic Study Re-Posted to YouTube

I have re-posted my comments and questions regarding the Mayo Clinic video on YouTube.

Questions Regarding Mayo Clinic Study Deleted from YouTube Video Post

My friend Bob, who has a terrific blog called Parkinson's Patients: Yes We Can Dance, recently drew my attention to a Mayo Clinic video on YouTube. In it, a physician named J. Michael Bostwick tells us that according to the findings of his recent study, at least one in every five people with Parkinson's who takes a dopamine agonist will experience compulsive behavior as a side effect.

That number is radically higher than any previous estimate, and given that even the lower numbers are completely unsupported by the evidence presented in any of the other papers I've ever read, i was curious. i read the study, something that, in general, i HIGHLY recommend to anyone with Parkinson's who is trying to make treatment-related decisions.

As I expected, there were some very curious aspects of this study, and a day or two ago I posted my observations, questions and criticisms of this study as comments to the YouTube video.

Today, I checked in on the video to find that my comments have been deleted.

So, I'm posting them below. I am planning a more comprehensive critique of the study, but wanted to get these comments back up on the Internet just in case anyone reads my newest post on theYouTube video post, which directs them here, before that comment is deleted, too. Here they are:

(I realize, reading these six items again today, that they probably won't make sense to anyone who hasn't read the study. However, I do want them available while I work on a post that will provide more explanation, so that it is clear that comments, criticisms, and questions that were deleted from the Mayo Clinic video post were rational, logical and posed in a civilized fashion.)

1) I beg everyone who sees this to read the actual study - not just the abstract, the whole study – it can be found here: http://www.ncbi.nlm.nih.gov/pmc/issues/177782/ - just scroll down a little – the pramipexole (Mirapex) package insert can be found here: http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/index.cfm?fuseaction=Search.Label_ApprovalHistory - check my facts, please!!

2) For 4 out of 7 patients, there is no stated temporal relationship btw initiation/increase or cessation/decrease in dopamine agonists & certain behavior – in the absence of a temporal relationship, on what basis are you claiming the existence of an association between the drug and the behavior?

3) 2 out of those 4, in addition to having no stated temporal relationship, are footnoted as “not clearly pathologic” – well, you cant’ have your cake and eat it too – if they aren’t pathologic, then they are not eligible for inclusion in a study with pathological as an inclusion criterion

4) you define 2mg/day or greater as therapeutic dosage of pramipexole – but according to the package insert, “doses of 3 mg, 4.5 mg, and 6 mg per day of MIRAPEX tablets were not shown to provide any significant benefit beyond that achieved at a daily dose of 1.5 mg/day.” So, actually, less than 2mg/day is definitely therapeutic.

5) You exclude 28 of the 66 people taking agonists on the basis of this never before heard and according to the package insert completely erroneous categorization of their agonist dosage as subtherapeutic.

6) If you remove the patients who were included without any basis for inclusion, and include those who were excluded without any basis for exclusion, you get 3 patients out of 66 taking dopamine agonists who experienced compulsive behavior, which indicates a prevalence of 4.5%, or approximately ¼ that which you are claiming to have found.

*Is* dopamine agonist therapy associated with pathological gambling?

Well, folks, I finally have corroboration from a doctor, published in a peer-reviewed journal (not that I think that means much, but others might) for my assertion that none of the gambling studies to date (which means as of 2007, or early 2008 at the latest), demonstrates the extent of risk of development of pathological gambling when taking dopaminergic meds. Dr. Zand says:

"Thus far, published reports have been able to neither demonstrate the extent of risk for gambling-related problems nor study the correlation of dosage with this potential adverse effect among Parkinson’s disease patients treated with dopaminergic medications."

My absolute favorite bit is this, with reference to the 2005 study by Dodd, et. al.:

"This report, however, did not include the total number of patients exposed to pramipexole, ropinirole or other dopamine agonist agents, so the incidence of pathological gambling could not be estimated."

Which is exactly what i said in my May, 5, 2008 blog entry Pathological Gambling Caused by Drugs Used to Treat Parkinson’s Disease: Yet Another Closer Look, Part Two, albeit not nearly so concisely.

I wonder why this paper didn't get any press whatsoever?

Zand R. Is dopamine agonist therapy associated with developing pathological gambling in Parkinson's disease patients? Eur Neurol. 2008;59(3-4):183-6. Epub 2008 Jan 29.

Pathological Gambling Caused by Drugs Used to Treat Parkinson’s Disease: Yet Another Closer Look, Part Three(a)

Welcome to Part Three(a) of a three part series.

To recap the background provided in Part One, in the 2005 study entitled “Pathological Gambling Caused by Drugs Used to Treat Parkinson’s Disease,” the authors mine records of Parkinson’s patients seen at the Mayo Clinic in Rochester, MN (MCR), between 2002 and 2004, and find 11 people who had developed pathological gambling (PG) - they conclude that the PG was caused by Parkinson's drugs. The authors so completely fail to provide evidence compelling enough to support this conclusion that the fact that this study was published in a peer-reviewed journal boggles the mind. It is available online for free at the Archives of Neurology, if you are interested. It may actually be necessary to read the study for what I am about to say to make sense – I don’t know.

According to the authors of this study, the 11 people who gambled fit the DSM-IV-TR criteria for PG.* They also say that the PG was temporally associated with the commencement, increase, and/or cessation of dopamine agonist (DA) therapy, a type of drug used to treat Parkinson’s disease (PD), and, for a disproportionate percentage of these people, the culprit was a DA called pramipexole.

Finally, the authors provide the results of their survey of the field of literature, and present in a table six studies in support of their conclusion that Parkinson’s drugs cause – not just “are associated with,” but cause PG.

In Part One, I addressed the authors’ failure to adequately support their central assertion, that DAs cause PG, in the context of what criteria must be met to identify a causal relationship. In Part Two, I addressed specifically the authors’ failure to provide any indication of the prevalence of this phenomenon and show how that pretty much single handedly invalidates the study. And in Part Three(a), I will address the authors’ failure to delineate the parameters of what they call a temporal relationship, and question the resultant inclusion of two of the 11 PGers.

I apologize for the enormous gaps between my posts but I write these things at night, and my meds are only carrying me through the work day in terms of typing. So, I may have to finish Dodd in more bite-sized bits.

Dodd et. al. base their assertion that there is a causal association between dopamine agonist (DA) therapy and pathological gambling (PG) on the presence of what they call a temporal relationship. A temporal relationship exists when Outcome Y follows the introduction of Variable X within a period of time that is considered plausible for a connection. Plausibility is determined by the natures of variable and the outcome – for example, if Outcome Y is deemed to be an allergic reaction and Variable X is a bee sting, the plausibility of their being related remains intact for a far shorter period of time than if Outcome Y is lung cancer and Variable X is smoking.

It should come as no surprise at this point that Dodd et. al. fail to delineate the parameters they use to identify the purported temporal relationship between DA therapy and PG. If we are curious, however, we should be able to infer them from the data provided, which is summarized in the table below:


With the help of common sense, it would seem reasonable to me to infer from the above that as long as either the latency of DA therapy initiation to gambling addiction (3rd column) or the latency of the discontinuation of DA therapy to the resolution of gambling (4th column) is less than or equal to 3months, the authors consider the possibility of a temporal relationship to be plausible – well, for most of the patients listed, anyway.

Patients 8 and 10 are different.

For Patient 10, even if we disregard the 2.5 year latency to PG onset, the authors ask us to stretch plausibility a minimum of 3 months in considering a latency to cessation of PG of up to 6 months after discontinuing DA therapy.

And – I am just going to say it – the inclusion of Patient 8, with her year-long latency to onset and the fact that they have no evidence that she ever stopped, is ludicrous.

And that brings the total number of people found to have started PG while taking PD meds down from 11 to 9, for whatever that is worth.

I think I will wrap up with a summary of what the studies Dodd et. al. cite in support of their conclusion really say but that will have to wait for another day.

*************************
* Pathological gambling is defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DMS-IV-TR) as follows, and the study does not describe in which five each patient has engaged:

A. Persistent and recurrent maladaptive gambling behavior as indicated by five (or more) of the following:

1. is preoccupied with gambling (e.g., preoccupied with reliving past gambling experiences, handicapping or planning the next venture, or thinking of ways to get money with which to gamble)
   
2. needs to gamble with increasing amounts of money in order to achieve the desired excitement
   
3. has repeated unsuccessful efforts to control, cut back, or stop gambling
   
4. is restless or irritable when attempting to cut down or stop gambling
   
5. gambles as a way of escaping from problems or of relieving a dysphoric mood (e.g., feelings of helplessness, guilt, anxiety, depression)
   
6. after losing money gambling, often returns another day to get even ("chasing" one's losses)
   
7. lies to family members, therapist, or others to conceal the extent of involvement with gambling
   
8. has committed illegal acts such as forgery, fraud, theft, or embezzlement to finance gambling
   
9. has jeopardized or lost a significant relationship, job, or educational or career opportunity because of gambling
   
10. relies on others to provide money to relieve a desperate financial situation caused by gambling
    

B. The gambling behavior is not better accounted for by a manic episode