Executive Summary
In short, that the last 40 years of research developing different iterations of levodopa were not geared toward improving on its strengths is evident in the incessant singing of its praises (and, since 1996 or so, its donning of the “gold standard” mantle). Rather, the last 40 years of levodopa-centricity have been focused on fixing all the things that are wrong with it.
And, in a nutshell, with respect to levodopa’s deficits, here is my assessment of what has been accomplished since 1970:
The transition from levodopa to Sinemet resulted in a 52% reduction in the incidence of nausea/vomiting, a 60% increase in the incidence of dyskinesias, and had no impact on wearing off or on/off fluctuations.
The transition from Sinemet to Sinemet CR resulted in no improvement in on/off fluctuations, a reduction in the frequency of dosing per day, and a 35% increase in the incidence of dyskinesias.
The transition from Sinemet CR to Stalevo resulted in – if you average the numbers from each of the clinical trials listed in the package insert – about 51 additional minutes of on time per day. It also resulted in a 75% higher incidence of dyskinesias, and that was only after six months.
So for the super duper summary, after 40 years of effort and untold amounts of money wasted trying to put bandaids on this shameful excuse for a “therapy,” the only real improvements that have been achieved are:
- a halving of the incidence of nausea/vomiting (1)
- a reduction in the number of times one has to take medication every day (2)
- and less than an hour of additional on time per day (3)
The four-fold increase in the incidence of dyskinesias pretty much wipes all of them out.
So – you tell me – has the Parkinson’s disease research community’s obsession with fixing levodopa paid off? [that is the end of the executive summary]
In Part II, each consecutive iteration of levodopa will be examined (4) to see exactly which deficits were targeted for improvement and how well those goals were achieved – an evaluation which requires examination of the effect of the change not only on the targeted deficits, but also on deficits not targeted for improvement.
Because levodopa’s prowess at ameliorating symptoms has never been questioned, I will not be including any examination of the effect of a change on motor scores – any improvements on that front have been gravy; they were not the stated goal of any of the changes, to my knowledge. Therefore, I will focus solely on the impact of 40 years of effort and countless dollars invested in the stated goal – fixing levodopa’s problems.
The milestones I will touch upon consist of either the marrying of levodopa with another drug in the same pill (Sinemet, 1975; and Stalevo, 2003) or actual reformulations of levodopa (Sinemet CR, 1991-2)
Sinemet
Levodopa was approved in 1970 or so. The next iteration in the US was approved in 1975, when Sinemet came on the market. One of the major problems with levodopa on its own was that it frequently caused what was termed “dose-limiting” nausea and vomiting. This was a consequence of the fact that most of the levodopa that was consumed was metabolized before it crossed the blood brain barrier, which meant one had to take what were referred to in one study as “massive oral doses” of the drug to ensure that the tiny percentage that made it to the brain was large enough to have an impact on symptoms. The addition of carbidopa, a decarboxylase inhibitor, to levodopa in 1975 inhibited the metabolizing of levodopa in the digestive tract, which allowed a larger percentage of a smaller dose to reach the brain intact and ready to be metabolized there. This made a big dent in the nausea problem. (1)(5)(6)
However, even way back then, levodopa’s other glaring deficits – dyskinesia (involuntary, uncontrolled muscle movements), wearing off (when the efficacy of the drug wears off before the next dose is due) and on/off fluctuations (when the efficacy of the drug suddenly and unpredictably disappears mid-dose (as opposed to at the end of the dose, which is termed “wearing off”)) - were evident and occurred at an alarmingly high rate – and quickly, too. For example, after one year on levodopa alone, observed rates of dyskinesia ranged from 41% to 60%. (7)(8)
And in their 1975 study, Lieberman et al noted that after two years, dyskinesias were observed in 48% of patients on levodopa, and were present in 77 % of patients on carbidopa/levodopa. That is a 60% increase, just in case you forgot your calculator today. (1)
The increase in dyskinesias might seem at odds with the fact that the decarboxylase inhibitor allowed a 75% reduction in the actual levodopa dose, but it makes perfect sense when one takes into account the fact that in spite of the smaller dose, more levodopa was actually getting to the brain. In fact, the ultimate effect of every improvement to date is that more levodopa gets to the brain.
Sinemet CR
The next improvement came in the form of Sinemet CR. CR stands for controlled release, which means that it is metabolized more slowly, thereby providing a more stable level of the drug in the bloodstream. This reduction of the fluctuation in the level of the drug in the bloodstream was sought after based on the theory that fluctuations in the levodopa plasma level (the amount of levodopa) in the bloodstream might contribute to the development of motor fluctuations (i.e., wearing off and on/off fluctuations). If you only just started reading about Parkinson’s and the latest theories being entertained by the research community, you might be under the impression that this theory (often described using the terms “continuous rather than pulsatile delivery” of the drug) was a relatively new one.
Hardly. The idea that there is an association between the two has been around since at least 1971 (9), and two different controlled release formulations were actually tested in 1978, with differing outcomes (10)(11).
For some reason, it was an additional 13 years before such a formulation was approved for use in the US, and given all that time, and the countless clinical trials undertaken to test out different controlled release formulations, and given that the whole purpose of the endeavor was to decrease the incidence of motor fluctuations, one would think that approval of Sinemet CR would indicate success on that front.
Think again.
The following is an excerpt from Sinemet CR product insert (the sheet of paper, packed with information about the drug, that is supposed to accompany each prescription that is filled) dated 1999:
“In clinical trials, patients with moderate to severe motor fluctuations who received SINEMET CR did not experience quantitatively significant reductions in o‘ ff ’time when compared to SINEMET (Carbidopa-Levodopa).” [sic]In fact, according to the table comparing the incidences of adverse experiences with Sinemet CR to those of Sinemet, the incidence of on/off fluctuations (as opposed to amount of time on or off) is almost 50% higher with Sinemet CR than with Sinemet.
And as far as dyskinesias go:
“Carbidopa does not decrease adverse reactions due to central effects of levodopa. By permitting more levodopa to reach the brain, particularly when nausea and vomiting is not a dose-limiting factor, certain adverse CNS effects, e.g., dyskinesias, will occur at lower dosages and sooner during therapy with SINEMET CR (Carbidopa-Levodopa) Sustained-Release than with levodopa alone.” [italicization per original]And:
“Patients receiving SINEMET CR may develop increased dyskinesias compared to SINEMET (Carbidopa-Levodopa).”Indeed, the table comparing the incidences of adverse experiences shows a 35% greater incidence of dyskinesias with Sinemet CR than with Sinemet.
Therefore, Sinemet CR, the whole point of which was to ameliorate motor fluctuations, has no effect on/off time (“on time” is when the drug is working and “off time” is when it is not), almost doubles the incidence of on/off fluctuations, and increases the incidence of dyskinesias by over 1/3.
So, while Sinemet CR is not completely without advantages – it does allow for less frequent dosing, after all – in my opinion they are obliterated by its deficits.
Stalevo
The most recent “improvement,” Stalevo (levodopa, carbidopa and entacapone, a COMT inhibitor (another compound that inhibits the metabolism of levodopa)), is also billed as enhancing the stability of the level of levodopa in the blood stream.
And, indeed, according to the package insert, one out of the three clinical trials listed did demonstrate a statistically significant improvement in on/off time (on increased/off decreased by 1.3-1.4 hours) with the addition of a COMT inhibitor. Of course, that means that the other two trials failed to show a statistically significant improvement in actual hours of on-time – though they do manage to squeeze some statistical significance out of the numbers by looking at the percent increase in on-time rather than the actual hours.
However, the incidence of dyskinesias is higher (surprise, surprise), and, in this instance, 75% higher, and the traditional solution to that problem, the lowering of the levodopa dose, failed to ameliorate that side effect in many patients – see the excerpt from the package insert below:
“Entacapone may potentiate the dopaminergic side effects of levodopa and may therefore cause and/or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa.”And that doesn’t even address the problem of how one reduces the levodopa dose alone when levodopa, carbidopa and entacapone are all rolled into one pill.
So, if we chart the “improvements” to levodopa, which, as I said, practically by definition were not targeted at its symptomatic benefit, we end up with something like this:
The transition from levodopa to Sinemet resulted in a 52% reduction in the incidence of nausea/vomiting, a 60% increase in the incidence of dyskinesias, and had no impact on wearing off or on/off fluctuations.
The transition from Sinemet to Sinemet CR resulted in no improvement in on/off fluctuations, a reduction in the frequency of dosing per day, and a 35% increase in the incidence of dyskinesias.
The transition from Sinemet CR to Stalevo resulted in – if you average the numbers from each of the clinical trials listed in the package insert – about 51 additional minutes of on time per day. It also resulted in a 75% higher incidence of dyskinesias, and that was only after six months.
So for the super duper summary, after 40 years of effort and untold amounts of money wasted trying to put bandaids on this shameful excuse for a “therapy,” the only real improvements that have been achieved are:
- a halving of the incidence of nausea/vomiting
- a reduction in the number of times one has to take medication every day
- and less than an hour of additional on time per day
The four-fold increase in the incidence of dyskinesias pretty much wipes all of them out.
In the next installment, I will consider how much money has been thrown at the eternally failing effort to fix levodopa, and how much money is currently being wasted on that same effort. I will also consider the question of whether there is any real incentive, given the size of the PD market, for any pharmaceutical company to risk its capital on a symptomatic therapy that is “better” than levodopa – an undertaking that has been deemed virtually impossible (whoever has been responsible for marketing levodopa has done an excellent job.)
(1) Lieberman A, Goodgold A, Jonas S, Leibowitz M. Comparison of dopa decarboxylase inhibitor (carbidopa) combined with levodopa and levodopa alone in Parkinson's disease. Neurology. 1975 Oct;25(10):911-6. Abstract.
(2) Sinemet CR Product Insert dated 1999.
(3) Stalevo Product Insert dated 2003.
(4) For statistics regarding motor complications with respect to Sinemet CR and Stalevo, the information I put forth is found on the product labeling – seems it would be difficult to argue with that. However, for the time period up to and including Sinemet’s introduction in 1975, my sources are limited to abstracts on PubMed, or the few studies published prior to 1980 I have been able to access on the internet. Studies that old are simply not available online, not even for a price.
(5) Wajsbort J, Dorner A, Wajsbort E. A comparative clinical investigation of the therapeutic effect of levodopa alone and in combination with a decarboxylase inhibitor (carbidopa) in cases of Parkinson's disease. Curr Med Res Opin. 1978;5(9):695-708. Abstract.
(6) Hanzal F. Treatment of Parkinson's syndrome with L-dopa and L-carbidopa. MMW Munch Med Wochenschr. 1976 May 14;118(20):653-6. Abstract.
(7) Markham CH, Treciokas LJ, Diamond SG. Parkinson's disease and levodopa. A five-year follow-up and review. West J Med. 1974 Sep;121(3):188-206.
(8) Shaw KM, Lees AJ, Stern GM. The impact of treatment with levodopa on Parkinson's disease. Q J Med. 1980;49(195):283-93.
(9) Allen JG, Calne DB, Davies CA, Reid JL. Relationship of plasma concentrations of levodopa to clinical response in Parkinsonsim. Br J Pharmacol. 1971 Oct;43(2):464P-465P.
(10) Saarinen A, Myllyla VV, Tokola O, Hokkanen E. Effect of a slow release preparation of levodopa on Parkinson's disease in combination with a peripheral decarboxylase inhibitor. Acta Neurol Scand. 1978 Dec;58(6):340-9. Abstract.
(11) Friedman A. [Preliminary assessment of the effectiveness of L-dopa with prolonged action (Medidopa retard) as compared to conventional L-dopa preparation] [Article in Polish]. Neurol Neurochir Pol. 1978 Jan-Feb;12(1):39-43. Abstract.
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