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The recent editorial1 supporting initial treatment of early onset Parkinson's disease with a dopamine agonist hinged in part on the demonstration2 in 268 patients that treatment of early onset Parkinson's disease with ropinirole alone or with supplementary levodopa/dopa decarboxylase inhibitor (benserazide) (LD/DDI) resulted in substantially less dyskinesia than with LD/DDI alone, with only slightly less motor benefit. Five per cent of patients on ropinirole alone developed dyskinesia after 5 years, compared with 25% with ropinirole plus LD/DDI, and 45% of those on LD/DDI alone). The trial design allowed LD/DDI supplementation if response was inadequate and additional trial drug could not be tolerated. Up to 24 mg ropinirole and 1200 mg LD/DDI daily were allowed. Sixty six per cent of patients completing the ropinirole arm required supplementation, the average mean daily dose of ropinirole at 5 years being 16.5 mg, compared with 753 mg of LD/DDI when the second was used alone.
It is unfortunate that the study required a three times daily dosage regime. It seems possible that this accounts for the surprising 33% of patients on LD/DDI alone who withdrew as a result of early adverse events, and for the occurrence of nausea in 49.4% of patients on LD/DDI alone. Whether smaller, more frequent, dosage would have allowed better tolerance of and motor response to ropinirole, it is not surprising that frequent dyskinesia was seen at 5 years on three times daily dosage of LD/DDI. A substantial proportion of patients on LD/DDI (43.8%) were also on selegiline, amplifying the effect substantially. By comparison, the 5 year study of immediate release (IR) and controlled release (CR) LD/DDI (carbidopa) in 681 patients, ironically reported earlier in 1997, and later in 1999,3 in whom dosage could be adjusted up to five or more times a day resulted not only in a lower frequency of dyskinesia (20.6% IR, 21.7% CR) at 5 years but also a lower mean total daily dose (426 mg IR; 510 mg CR (bioequivalent)).
Whereas it may be argued that different drug preparations and methods of assessment invalidate comparison, it may be simply that less frequent higher pulsatile dosage provokes not only greater peak dose dyskinesia but also, as a mirroring effect, greater off time as postsynaptic mechanisms adapt to cope with surges of dopamine and perhaps lose sensitivity to troughs. Patients seen during troughs would be liable to have their dose increased. If the interdose interval were fixed this would lead to a vicious circle.
Given reports of long term resolution of dyskinesia and on/off effects in response to various methods of continuous stimulation, at an appropriate strength, including continuous daytime jejunal infusion of LD/DDI (with little or no change in LD/DDI dosage requirement over 57 months),4 and of a neuroprotective effect of levodopa,5 the results of Rascol et al 2 should not dissuade others from pursuing oral treatment with LD/DDI in a more frequent, lower dose regime. With gradual (allowing for the long duration action of levodopa) titration of slow release LD/DDI dosage and interdose interval (if necessary using a timer), against response and compliance of patient (or carer), it may in theory and, with sufficient observation and titration, in practice be possible to approximate to such a steady state stimulation and response. This would have potentially less risk for developing hallucinations, and would cost less.
Ponsford seems to focus primarily on the design and findings of the 056 trial of ropinirole versus levodopa in early Parkinson's disease recently reported in the N Engl J Med 1-1 rather than the editorial as a whole; however, to take up his points:
Firstly, he suggests that it is unfortunate that the 056 trial required a three times daily levodopa dosage regime as use of more frequent smaller doses could have reduced the incidence of dyskinesias. We chose a three times daily regime in part to match the three times daily regime of ropinirole and also because it was thought that this regime reflected common clinical practice in patients with early Parkinson's disease. A trial formally comparing use of multiple low doses of levodopa versus a three times daily medium dose regime in early Parkinson's disease would, however, be of great interest. It might well be that the multiple low dose approach in early disease would spare complications but this has yet to be shown. Addition of a catechol-O-methyltransferase inhibitor to smooth out the plasma levodopa profile in early Parkinson's disease might also prove beneficial.
Secondly, he suggests that the allowed presence of selegeline may have magnified the tendency of levodopa to cause complications. This could indeed be the case although stratifying for selegeline usage in the levodopa arm did not highlight any such effect.
Thirdly, he suggests that allowing the use of slow release levodopa preparations in early Parkinson's disease could have been beneficial. There is currently no trial data to support this viewpoint; on the contrary, early use of either slow release madopar or sinemet has been reported to be associated with a similar prevalence of complications as the use of standard preparations.
My current feeling is that early use of dopamine agonists in suitable patients with Parkinson's disease remains a reasonable strategy to delay complications. It may well be that in the future, however, a more optimal way of delivering levodopa is devised which achieves continuous and uniform dopaminergic stimulation and so reduces the prevalence of fluctuations and dyskinesias.