Wednesday, April 8, 2009

They Should Have Seen This Coming

In the April 2009 issue of Mayo Clinic Proceedings (1), a research article titled, "Frequency of New-Onset Pathologic Compulsive Gambling or Hypersexuality After Drug Treatment of Idiopathic Parkinson Disease" was published. More specifically, the authors looked at two dopamine agonist drugs (i.e., pramipexole & ropinirole). There are many other dopamine agonist on the market (e.g., bromocriptine, apomorphine), but since those drugs are old (and cheaper), they are not prescribed as widely as the newer (and more expensive) drugs. Pramipexole (Mirapex) and ropinirole (Requip) are prescribed for Parkinson's disease, but are heavily advertised for the bogus condition, restless leg syndrome* (RLS; 2, 3).

Here's what they found. "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. Behaviors abated with discontinuation of agonist therapy or dose reduction."

Anyway, don't you think that compulsive gambling and hypersexuality are pretty weird "side effects?" (Binge eating is another common side effect).

As it turns out, not all dopamine agonist are created alike. Typically, they fall into two categories, ergot derivatives and non-ergot derivatives (apomorphine is a morphine derivative). Ergot is a substance produced by the parasitic fungus Claviceps purpurea (common in rye and wheat). LSD is synthesized from ergot (which is good stuff by the way). Pramipexole and ropinirole are non-ergot derivatives, while bromocriptine is an ergot derivative.

The dopaminergic system is comprised of 5 different dopamine receptors (D1-5). D2 agonism is the primary method of treating Parkinson's disease and RLS. Pramipexole and ropinirole have affinities (i.e., chemical attraction) for the D3 receptor, and then the D2 receptor. Bromocriptine primarily has a high affinity for the D2 receptor, and apomorphine has a high affinity for the D1 receptor, followed by the D2 receptor. As the late, great, last psychiatrist discussed (4), if a drug has multiple affinities (e.g., D3 & D2), that specific receptor system will need to be saturated before the other receptors are affected. It other words, with Pramipexole and ropinirole, the majority of the D3 receptors in the brain will become stimulated before the D2 receptors.

Here is where this story gets interesting (that's if you find this shit interesting): The D3 receptor is primarily found in the nucleus accumbens. This is the part of the limbic system that helps to modulate emotional behavior and also plays an important role in the rewarding and reinforcing effects of many abused drugs (and other behaviors such as eating and sex). Moreover, the D3 receptor is the most sensitive to stimulation, requiring less dopamine to generate action potentials.

To the best of my knowledge, it's only the dopamine agonist that stimulate D3 that have the associated "side effects" of compulsive gambling, hypersexuality, and binge eating. I have not seen any reports that bromocriptine and apomorphine have these side effects (5, 6, 7 , 8).

What we have, is a situation where people with a legit disease (i.e., Parkinson's disease) are getting treatment from a drug that, before the therapeutic receptor is stimulated, the behavioral reinforcing receptor gets stimulated and saturated first.

Bromocriptine and apomorhpine are older drugs and have been used on Parkinson's patients for a quite a while. Pramipexole and ropinirole are newer and are the only drugs in the US approved for the specter that is RLS. As is the pattern, when docs start prescribing a drug for one condition, they will prescribe it for other conditions as well (any psychiatric drug fits this model). By pushing these drugs for RLS (a vague and amorphous condition), docs will, by extension, prescribe these drugs for Parkinson's disease too, while the older drugs are prescribed less often.

A months supply ( 60 tablets) of pramipexole (1mg for twice a day) costs approximately $170. A month's supply of ropinirole (3mg twice a day) cost approximately $180 (the drug recently went generic, so it should be cheaper soon). A month's supply of bromocriptine (5mg once a day) costs $130. Apomorphine is mainly administered by injection or pump, so a price cannot be provided.

I know what you're thinking, $40 or $50 is not a huge difference. Except, when you realize that some of the patients who developed compulsive gambling lost close to $60,000. A large price to pay for a drug that's probably no more effective than what's already been on the market for years.

I have not been able to find any comparator trials for bromocriptine, apomorphine, pramipexole, and ropinirole. So, why prescribe the newer drugs when nothing seems to be wrong with the older drugs? The side effects of compulsive gambling and hypersexuality arose after the new drugs had gone to market. Docs were prescribing the drugs without knowing the true risks (as is the case with any new drug). This is a common practice; out with old, in the new. It doesn't seem to matter that no evidence exist to indicate that new drugs are more effective than old drugs.

Here is my main point: I'm an idiot (not my main point); if I can look up the affinities of these two drugs on wikipedia (9, 10), and then deduce how they can cause these "side effects," the people who developed these drugs should have seen this controversy coming (that's my main point). It appears as if marketing, not science, was the prevailing force here, once again.

Here's another crime against the sick: The FDA (The Federal Douche-bags of America) recently approved tetrabenazine-TBZ (Xenazine) for the treatment of chorea associated with Huntington's disease (Was that the drug 13 was on?). This drug has been available in other countries for decades (which means it should be cheap). "A years' supply of TBZ at a dose of 50mg/day will cost about $40,000" (11). Fuck! The pharmaceutical industry is the largest single lobbying sector in Washington DC (12). As a result, not only do Americans pay more money for their medications than other nations; we also cannot import drugs produced in other countries, or re-import drugs that were originally manufactured in this country. The cocksuckers!

* To people diagnosed with RLS, I have two things to say: Firstly, it was not my intention to diminish your suffering, as I acknowledge that it is real suffering; and secondly, fuck you!

To people diagnosed with chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivities, toxic mold and sick building syndrome, and Persian gulf war syndrome; the above applies to you too.

UPDATE: Another study showing the same thing. Waste of time and money (13)

(image credit: Anthony Flores)

1. J. Michael Bostwick, MD,, 2. Kathleen A. Hecksel, MD,, 3. Susanna R. Stevens, MS,, 4. James H. Bower, MD and, & 5. J. Eric Ahlskog, MD, PhD (2009). Frequency of New-Onset Pathologic Compulsive Gambling or Hypersexuality After Drug Treatment of Idiopathic Parkinson Disease Mayo Clinic Proceedings

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Anonymous said...

On a lark, I just called my local Rite Aid; the per pill price on Xenazine (25mg) is $75 each. Your 50mg/day scenario would be two pills/day ($150/day) x 365 days = $54,750. NOTE: the Rite Aid Discount Card gets you 20% off, so that would save about $10k, leaving you with a $43,800 annual bill to control your chorea. Assuming you don't have health insurance of course (which isn't hard to imagine for HD patients.)

Anonymous said...

Addendum to previous comment:
By comparison, has the brand Xenazine at a per pill price of $2.33 (USD), and a per pill price for Generic Tetrabenazine of $1.75 (USD).
In USD, that's $1,280 per year for 50mg of Generic Tetrabenazine and $1,700 per year for 50mg of the brand name Xenazine. U.F.B.

NeuroPsych15 said...

Thank you for proving my point.

Neuroskeptic said...

In the UK quite recently, there was a case of a man who developed a child porn obsession after starting on Parkinson's meds. He got caught and he pleaded diminished responsibility and got aquitted. It led to some quite fun headlines along the lines of "Pedo says: pills made me do it!"

Marilyn Mann said...

"and secondly, fuck you!" Um, why?
I don't get it.

NeuroPsych15 said...

Marilyn: I don't get it either. I usually have a couple of glasses of bourbon (90 proof) in me when I write these things.

Mike said...
This comment has been removed by the author.
Anonymous said...

Bromocriptine does cause hypersexuality and gambling problems .I take bromo for a pituitary tumor (10 mgs ) a day and developed insane hypersexuality(dosage was lowered to 5mgs and it completely went away).I had no desire to gamble though.Also experienced mania while on bromo which is also a cause of hypersexuality.I am married and the whole thing is really a big issue.May seem funny but disrupts lives and families.SCARY AND EMBARASING.