Early Parkinson's Disease
Amantadine is generally considered as a mild antiparkinsonian agent, with effects on tremor, rigidity, and bradykinesia, and a well-tolerated side-effect profile. It is used in early PD when considering levodopa sparing strategies or when symptoms are mild enough not to warrant more aggressive therapy. Amantadine has been studied in early PD as monotherapy, and in combination with anticholinergics in limited series and small controlled studies, with relatively short follow-up (18-20). However, review of randomized controlled trials of amantadine does not reveal sufficient evidence to support its efficacy in the treatment of early PD (21,22). The 2002 American Academy of Neurology guidelines for the initiation of PD treatment did not discuss the use of amantadine (23).
Part of the rationale for considering amantadine monotherapy are suggestions that it may have neuroprotective properties to slow the progression of PD. Uitti et al. found that amantadine use was an independent predictor of improved survival in a retrospective analysis of all parkinsonism patients (92% PD) treated with amantadine compared to those not using this medication. The results are suggestive of either an ongoing symptomatic improvement or the presence of inherent neuroprotection (24). There has been no confirmatory evidence to suggest neuroprotection from studies in PD patients.
Advanced Parkinson's Disease
Use of amantadine in managing PD motor complications was first described in 1987 by Shannon et al. (3) in a small open-label study. They reported improved motor fluctuations using a qualitative scale, examining on and off function in 20 PD patients. This notion has gained further support from Metman et al. who reported the results of double-blind, placebo-controlled, cross-over studies of amantadine in a small cohort of 14 PD patients. There was a 60% reduction in both peak dose dyskinesia and severity of off periods, along with a decreased duration of off time (25). One year later, these patients had maintained significant benefit (5). The Cochrane database systematically reviewed randomized controlled studies (26) that evaluated amantadine versus placebo in the treatment of levodopa-induced dyskinesia, and reported a lack of evidence to support the efficacy of amantadine. Thomas et al. (27) conducted a double-blind, placebo-controlled study in 40 PD patients and concluded that 300 mg of amantadine was effective to control levodopa-induced dyskinesia by approximately 45%; however, the effect was maintained for less than eight months in all patients. Another randomized, double-blind, controlled study (28) of 18 PD patients found that the duration of levodopa-induced dyskinesia was reduced by using amantadine. The recognition of different dyskinesia phenomenology may be important in the response to amantadine. For instance, dystonic dyskinesia has shown varied inter-individual effects in a few studies (3,4). Also, specific efficacy for sudden on-offs or biphasic dyski-nesia has not been formally investigated.
Recent evidence suggests that amantadine produces its antidyskinetic effects via a glutamate N-methyl-D-aspartate (NMDA) antagonism (29). This independence from dopaminergic mechanisms was proposed as an explanation for the ability of amanta-dine to ameliorate levodopa-induced dyskinesia without worsening parkinsonism (25).
One frequent assumption about amantadine is that it offers only transient efficacy that typically lasts less than a year. However, this apparent loss of efficacy for ameliorating parkinsonian symptoms was reviewed and attributed largely to the progression of the disease itself. It has also been reported that early-stage PD patients may be treated effectively for years with amantadine, and still find that their symptoms noticeably worsen following drug withdrawal (16).
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