Antidyskinetic actions of amantadine in Parkinson’s disease: are benefits maintained in the long term?

Abstract

Evaluation of: Wolf E, Seppi K, Katzenschlager R et al. Long-term antidyskinetic efficacy of amantadine in Parkinson’s disease. Mov. Disord. DOI: 10.1002/mds.23034 (2010) (Epub ahead of print).

Amantadine remains the principal pharmacological approach to reducing L-DOPA-induced dyskinesia in Parkinson’s disease (PD). Owing to the way amantadine use has evolved over time, essentially a switching indication from an anti-parkinsonian to an antidyskinetic use, without any regulatory requirement to demonstrate antidyskinetic efficacy at Phase III, remarkably little is known about its actions. Thus, while several Phase II-like, proof-of-concept studies provide high quality data to support amantadine efficacy in dyskinesia after acute administration, there are few data to show these effects are maintained over time, and none beyond 1 year. The study by Wolf et al. is the first to assess the efficacy of amantadine in reducing dyskinesia in PD patients whose duration of amantadine therapy is in the range of 4–5 years. They clearly demonstrate that the antidyskinetic benefits of amantadine are maintained for this length of time. Amantadine is likely to continue to be a useful component of the therapeutic armamentarium that can be employed in PD.

Keywords::

• amantadine
• dyskinesia
• Parkinson’s disease

Dopamine replacement therapy, particularly with the dopamine precursor 3,4,-dihydroxyphenylalanine (L-DOPA), has been the mainstay of symptomatic therapy in Parkinson’s disease (PD) for more than 40 years. Despite its obvious success in combating the core motor symptoms of PD, the benefit of dopamine-replacement therapy is compromised, especially with repeated treatment in advancing disease, by a range of motor and non-motor complications. Foremost amongst these are involuntary movements, L-DOPA-induced dyskinesia. In the 1990s, an increased understanding of treatment-related dyskinesia in PD focused upon enhanced glutamatergic signaling, especially at NMDA receptors, in the striatum as being central for the expression of dyskinesia. This raised the possibility that an NMDA receptor antagonist might provide benefit as an adjunctive therapy in PD to suppress the expression of dyskinesia, while allowing the anti-parkinsonian benefit. It was realized around the same time that amantadine, a drug used for decades, although with limited benefit, in the treatment of the hypokinetic motor symptoms of PD, was actually an NMDA receptor antagonist. Studies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkey model of PD demonstrated the potential of amantadine to reduce L-DOPA-induced dyskinesia [1]. These findings were rapidly translated into Phase II success, initially by two groups, including the group that published the work being reviewed here [2,3]. Given that amantadine was already available in many territories, Phase III studies were not required to switch from an anti-parkinsonian to an antidyskinetic indication, and amantadine became the first drug widely-used to suppress treatment-related dyskinesia in PD. Given this somewhat unorthodox development path, the number of randomized, controlled clinical studies assessing efficacy of amantadine for dyskinesia in PD is limited, although there have been several Phase II-like studies confirming efficacy in small numbers of patients. There has been some debate, although little data, on whether the antidyskinetic actions of amantadine are maintained over time. This is a pertinent question, as the anti-parkinsonian actions of amantadine were, in the past, typically considered to wane over the course of months. Prior to this study, the only well-controlled data on the duration of amantadine benefits against dyskinesia, suggested that benefits were maintained for up to 1 year [4]. While promising, and rejecting the possibility of rapid tachyphylaxis, these data did not allow the community to assess the true potential of amantadine to manage dyskinesia over many years. These questions become increasingly important as the promise of new antidyskinetic drugs that might supersede amantadine has not been met. The study of Wolf et al. addresses the issue of whether the antidyskinetic results of amantadine are maintained in the longer, 4–5-year, timeframe [5].

Methods & results

In total, 38 patients with PD were recruited from seven centers across Austria. After screening, 32 patients enrolled in the study. All patients had L-DOPA-induced dyskinesia that was being treated with amantadine. The dose of amantadine had been stable for at least a year in each patient and, on average, was approximately 300 mg/day. The mean duration of disease was approximately 17 years, of which L-DOPA had been given for 13.4 years and dyskinesia was apparent for 6.5 years. Amantadine therapy had been given for approximately 5 years. Patients were randomized to two groups. The first continued treatment with amantadine (dose unchanged), the second was switched to placebo. During the test period of the study, both placebo and amantadine were identical in appearance, and different to pretrial amantadine. Assessments were made at baseline and after 3 weeks of drug treatment. The primary efficacy end point of the study was the dyskinesia severity components of the Unified Parkinson’s Disease Rating Scale (Part IV, items 32 and 33).

Of the 32 patients enrolled, 28 completed the study (per protocol population). In the intention-to-treat population, the switch from amantadine to placebo led to a significant worsening of dyskinesia. Thus, Unified Parkinson’s Disease Rating Scale Part IV items 32 and 33 was significantly increased by 39% (from 3.1 to 4.3). Similarly, there was a significant increase in ‘on’ time with troublesome dyskinesia, by 106% (from 1.7 to 3.5 h). By contrast, in patients remaining on amantadine, there were no significant increases in any parameters related to dyskinesia. The per protocol population data were similar and likewise demonstrated an exacerbation of dyskinesia after 3 weeks washout of amantadine.

Discussion & significance

The study was well conducted and all relevant methodological consideration appears to have been addressed. The data clearly support the idea that amantadine therapy, even after a duration of 4–5 years, can provide benefit in reducing the problem of dyskinesia in PD. This is important as, more than 10 years after the first demonstration of antidyskinetic efficacy in human, amantadine remains the only widely used antidyskinetic agent in PD. The data should help remove the perception, which is based on anecdote, and not well-controlled, data, that amantadine effects wear off rapidly. The data extend the length of time that benefits of amantadine can be expected, from 1 year to over 4.5 years.

The use of a double-blind washout design is innovative, within the PD field, and makes good use of a population of patients with long-term treatment. The data also highlight that discontinuation of amantadine therapy could have a negative impact on patients and that exacerbation of dyskinesia is a potential outcome of such a change.

However, the data presented do not show that amantadine is effective in reducing dyskinesia in all patients with dyskinesia. The population under study is quite a selective one, that is, patients that have been maintained on amantadine therapy for, on average, 4–5 years. Presumably, there is a potential for selection bias towards patients who can firstly tolerate amantadine well and secondly gain benefit from it. That said, this does not diminish the basic, and important, conclusion of the study that, in those who benefit, one can expect the benefit to be maintained for many years.

Expert commentary & five-year view

This latest report clearly demonstrates that patients obtaining antidyskinetic benefit from amantadine can expect to have maintained benefit in the long term. Concern of rapid tachyphylaxis seems unfounded. This is good news for the PD community. However, the work offers little new insight into the population of PD patients with L-DOPA-induced dyskinesia who can benefit from amantadine. Clinical practice suggests that those benefiting from amantadine might be a subset of all PD patients with L-DOPA-induced dyskinesia. Randomized controlled Phase III-type trials would be required to ascertain this. Given the development status of amantadine, this is unlikely to happen. This issue highlights the unique position of amantadine in that it has not had to cross the Phase III hurdle in reaching the market as a treatment for dyskinesia in PD. Although, amantadine is approved for treatment of PD, it is not, nor is any drug to date, approved specifically for an indication of reducing dyskinesia in PD. The current clinical availability of amantadine relies on historical approval that did not require demonstration of efficacy against dyskinesia. I anticipated 5 years ago that, by now, amantadine would have been replaced by more efficacious and selective agents that would alleviate dyskinesia in a broader population. Indeed, many compounds, of several drugs classes, have been shown to reduce L-DOPA-induced dyskinesia in the MPTP-lesioned non-human primate model of PD. Methodologies have been developed, both preclinically and clinically, that have made use of the MPTP-primate as an excellent means of defining efficacy in PD patients at Phase II. Thus, in addition to amantadine, several drugs, including idazoxan, fipamezole, quetiapine, clozapine, sarizotan and nabilone, have been shown to reduce dyskinesia in both MPTP-lesioned non-human primates and in randomized controlled Phase II clinical studies. Unlike amantadine, these agents were generally not already available in the clinic and, thus, faced the challenge of Phase III before they could be approved for marketing (the one exception is clozapine, which can be used, and is chosen, as an alternative to amantadine by some clinicians. However, its use has not been widely taken up, perhaps in part due to the risk of agranulocytosis and the need for monitoring). The translation of MPTP primate and Phase II success to Phase III success has proven surprisingly difficult for antidyskinetic agents in PD. Most recently, two studies with sarizotan were unable to demonstrate antidyskinetic efficacy, despite excellent Phase II proof-of-concept. Many issues probably underlie the difficulties of Phase III translatability, but it is likely that different evaluation tools are needed if the promise of the next generation of antidyskinetic agent is to be met and amantadine is superseded. It seems likely that the next 5 years will see further efforts to define such methodology, for instance moving away from diary measures of ‘on’ time with troublesome dyskinesia and towards more clearly defined measures of impact of dyskinesia on quality of life and, perhaps, better defining inclusion criteria so that studies employ patient populations for whom dyskinesia impacts significantly on quality of life. The next 5 years will thus see the continued use of amantadine as front-line pharmacotherapy for dyskinesia in PD. The article reviewed here suggests that patients initiating amantadine therapy today, and experiencing benefit of that therapy, will enjoy maintained benefit for at least 5 years.

Key issues

• • Amantadine is the principal pharmacological approach to reducing 3,4,-dihydroxyphenylalanine-induced dyskinesia in Parkinson’s disease.

• • Remarkably little is known about whether the antidyskinetic actions of amantadine are maintained over time.

• • The study by Wolf et al. suggests that the duration of amantadine benefit against dyskinesia can be observed for at least 4–5 years.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.