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.

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* 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

Evidence-based Medicine - Is This New?

I am hearing this catch phrase fairly regularly recently, and I have to ask - is this actually something new? i mean, newer than, say, 50 years old, at least? Because if it is, good lord what has medicine been based on up until now? Tea leaves? Magic 8 balls? The whims of medical practitioners? Old wives' tales? All those millions of research studies that have been undertaken in the last half century - were they done purely for their entertainment value?

I must be missing something.

Pathological Gambling Caused by Drugs Used to Treat Parkinson’s Disease: Yet Another Closer Look, Part Two

Welcome to Part Two 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 will address 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, I will address several other questions that come up when one actually reads the study rather than the press coverage it received.

Prevalence is defined by the Centers for Disease Control as “the number of existing disease cases [or, in this case, adverse events of a specific nature] in a defined group of people during a specific time period.”

So there are three parts to prevalence, each of which consists of a number – (1) the number of existing cases; (2) a defined [read: finite, i.e., quantifiable] group of people among whom those cases are found; and (3) a specific time period.

Prevalence is calculated by dividing the number of existing cases by the quantity of people in the specific population in which those cases were found, which yields a percent of people affected. In this study, the authors provide the number of existing cases, which is 11, and they denote a specific time period, which is 2002 to 2004. However, the authors omit (2), the total number of people with Parkinson’s (PWP) being treated at MCR and taking DAs between 2002 and 2004, and that really makes the claim that an association was found groundless.

In order to illustrate why this is true, and because I was unable to find any relevant stats regarding the MCR, I extrapolated a value for the missing piece of data from information found in various places on the internet, and using this method (which I have detailed below, in case you are interested)** I came up with the number 1195 for the total number of PWP taking DAs that were seen at MCR between 2002 and 2004. 11/1195 returns a prevalence of PG of 0.09% among those who were taking DAs.

But even that is not enough information. The authors also fail to provide the prevalence of PG in the general population or in untreated PD, which is just as crucial as the total number of (PWP) being treated at MCR and taking DAs between 2002 and 2004, because the only way a prevalence in a certain population has meaning is in relation to the prevalence of the same phenomenon in a different population.

So, I looked around and found the following stats for the general population from 1999. Estimates of the lifetime prevalence of PG in the general population in the US in the late 90s range from 1.2-3.9%, while estimates of past year prevalence of PG in the general population range from 0.6-2%.***

As you might have noticed, the prevalence I have extrapolated for the 11 who gambled is far lower than even the lowest estimated prevalence I could find for the general population. One might argue that my method of deriving that prevalence was not scientific, and that may be true.

However, in the absence of the total number of (PWP) being treated at MCR and taking DAs between 2002 and 2004, there is no way of knowing whether the prevalence of PG among those taking DAs is higher or lower than that of the general population.

And if the prevalence really were 0.09%, i.e., significantly lower than that of the general population, then I would think the makers of pramipexole would be doing the victory dance, because they would then be purveyors of a treatment for, not a cause of, PG.

And it is in that way that the authors fail to provide evidence sufficient and compelling enough to support their conclusion.

If I have not explained my thoughts clearly, please let me know and I will try again.

On to Part Three.

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* 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


**Based on the fact that Ohio State University’s Dept of Neurology’s 28 physicians see 400 PWP annually, I will extrapolate that the 93 neurologists at MCR see 1328 PWP annually, or 3984 PWP over the three year period in question. And according to the website of a law firm selling its services to folks who have gambled while taking a DA, 30% of PWP are prescribed DAs – which would mean 1195 people on DAs were seen at MRC between 2002 and 2004.

*** 3.9% lifetime; 2% past year ~ National Research Council. Pathological Gambling: A Critical Review. Washington, DC: National Academy Press; 1999

1.2% lifetime; 0.6% past year ~ National Opinion Research Center at the University of Chicago, Gemini Research, and The Lewin Group. Gambling Impact and Behavior Study. Report to the National Gambling Impact Study Commission. April 1, 1999. Table 7, p. 26.

Pathological Gambling Caused by Drugs Used to Treat Parkinson’s Disease: Yet Another Closer Look, 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 it 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 will address the central assertion, that DAs cause PG, in the context of identifying a causal relationship. In Part Two, I will address the significance of prevalence in that endeavor. And in Part Three, I will address several other questions that come up when one actually reads the study rather than the press coverage it received.

I am probably not telling you anything new when I say that researchers, or responsible ones, at least, can’t just declare that X causes Y, they have to – or are supposed to - prove it, or at least put forth compelling supporting evidence.

Nor can they themselves willy-nilly decide what is compelling and what isn’t – while there is some leeway, there are certain gauges that are accepted as valid, and the degree to which their evidence measures up on those gauges determines its persuasiveness.

One such gauge is Naranjo’s algorithm, which consists of a series of questions to which each possible answer (yes/no/unknown) is assigned a different number of points, thereby weighting the each answer according to its significance. In the end, the total number of points indicates how compelling the evidence is. Below is how this particular study fares using Naranjo’s algorithm:



As you can see, the evidence provided in this study is not compelling enough to indicate even a probable association, never mind definite, or causal, association.

Another set of guidelines can be found on the World Health Organization’s web site – following each bullet point below are my comments on how compellingly the evidence presented in this study fulfills these criteria:

Building on the seminal work on determining causality of the Surgeon General’s Advisory Committee on Smoking and Health (1964),3 the generally established criteria underpinning vaccine [or, in this case, drug] adverse event causality assessment that the GACVS uses may be summarized as follows:

• Consistency. The association of a purported adverse event with the administration of a [drug] should be consistent, i.e. the findings should be replicable in different localities, by different investigators not unduly influencing one another, and by different methods of investigation, all leading to the same conclusion(s).
  
  This study was preceded by a single other study which claimed to have found the same association. Even if that single study had adequately supported its conclusion (which it did not), it would obviously fail to provide what could be called consistency of any sort.
  
  
• Strength of the association. The association should be strong in the magnitude of the association (in an epidemiological sense), and in the dose-response relationship of the [drug] with the adverse effect.
  
  The authors do not provide the information necessary to evaluate the magnitude of the association, i.e. prevalence – see Part Two.
  
  
• Specificity. The association should be distinctive ñ the adverse event should be linked uniquely or specifically with the [drug] concerned, rather than its occurring frequently, spontaneously or commonly in association with other external stimuli or conditions.
  
  PG occurs frequently, spontaneously, and commonly in association with other external stimuli or conditions, like depression and disability.
  
  
• Temporal relation. There should be a clear temporal relationship between the [drug] and the adverse event, in that receipt of the [drug] should precede the earliest manifestation of the event or a clear exacerbation of an ongoing condition. For example, an anaphylactic reaction seconds or minutes following immunization would be strongly suggestive of causality; such a reaction several weeks after vaccination would be less plausible evidence of a causal relation.
  
  The authors neglect to define any parameters for identifying a temporal association, and indeed inclusion of three of the eleven on that basis stretches the bounds of plausibility past the breaking point.
  
  
• Biological plausibility. The association should be coherent; that is, plausible and explicable biologically according to known facts in the natural history and biology of the disease.
  
  There are those who point to the role of dopamine in addiction, but there are serious questions that remain not only unanswered, but unasked. For example, if one’s medication is maintaining an appropriate level of dopamine in the brain, why would one be any more vulnerable to addiction than anyone else?

Clearly, the evidence presented In this study, as evaluated by two widely respected and utilized measures, is not nearly compelling enough to support the conclusion that there is a causal relationship between DAs and PG. But if that doesn’t convince you, read on to Part Two. ****** * 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