Recent Clinical Advances in Pharmacotherapy for Levodopa-Induced Dyskinesia
Onset of involuntary movement patterns of the face, body and limbs are known as dyskinesia. They mostly appear in association with long-term levodopa (l-dopa) therapy in patients with Parkinson’s disease. Consequences include patient distress, caregiver embarrassment and reduced quality of life. A severe intensity of this motor complication may result in troublesome disability; however, patients typically prefer motor behaviour with slight, non-troublesome dyskinesia to ‘OFF’ states. Pharmacotherapy of dyskinesia is complex. Continuous nigrostriatal postsynaptic dopaminergic receptor stimulation may delay onset of l-dopa-associated dyskinesia, while non-physiological, ‘pulsatile’ receptor stimulation facilitates appearance of dyskinesia. In the past, there have been many clinical trial failures with compounds that were effective in animal models of dyskinesia. Only the N-methyl-d-aspartate antagonist amantadine has shown moderate antidyskinetic effects in small well-designed clinical studies. Amantadine is an old antiviral compound, which moderately improves impaired motor behaviour. Recently, there has been a resurgence of its use due to the US Food and Drug Administration approval of an extended-release (ER) amantadine formulation for treatment of l-dopa-induced dyskinesia. This pharmacokinetic innovation improved dyskinesia and ‘OFF’ states in pivotal trials, with a once-daily oral application in the evening. Amantadine ER provides higher and more continuous amantadine plasma bioavailability than conventional immediate-release formulations, which require administration up to three times daily.
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Conflict of interest
TM. and J.-D.M. have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the article. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
- 4.Przuntek H, Müller T, Riederer P. Diagnostic staging of Parkinson’s disease: conceptual aspects. J Neural Transm (Vienna). 2004;111(2):201–16.Google Scholar
- 5.Müller T, Öhm G, Eilert K, Möhr K, Rotter S, Haas T, et al. Benefit on motor and non-motor behavior in a specialized unit for Parkinson’s disease. J Neural Transm (Vienna). 2017;124(6):715–20.Google Scholar
- 33.Katzenschlager R, Poewe W, Rascol O, Trenkwalder C, Deuschl G, Chaudhuri KR, et al. Apomorphine subcutaneous infusion in patients with Parkinson’s disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2018;17(9):749–59.PubMedGoogle Scholar
- 37.Verhagen Metman L, Del Dotto P, LePoole K, Konitsiotis S, Fang J, Chase TN. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol. 1999;56(11):1383–6.Google Scholar
- 38.Verhagen ML, Del Dotto P, van den Munckhof P, Fang J, Mouradian MM, Chase TN. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology. 1998;50(5):1323–6.Google Scholar
- 46.Chase TN, Bibbiani F, Oh JD. Striatal glutamatergic mechanisms and extrapyramidal movement disorders. Neurotoxicol Res. 2003;5(1–2):139–46.Google Scholar
- 56.Hauser RA, Pahwa R, Tanner CM, Oertel W, Isaacson SH, Johnson R, et al. ADS-5102 (Amantadine) Extended-Release Capsules for Levodopa-Induced Dyskinesia in Parkinson’s Disease (EASE LID 2 Study): interim results of an open-label safety study. J Parkinsons Dis. 2017;7(3):511–22.PubMedPubMedCentralGoogle Scholar
- 66.Kraus MF, Smith GS, Butters M, Donnell AJ, Dixon E, Yilong C, et al. Effects of the dopaminergic agent and NMDA receptor antagonist amantadine on cognitive function, cerebral glucose metabolism and D2 receptor availability in chronic traumatic brain injury: a study using positron emission tomography (PET). Brain Inj. 2005;19(7):471–9.PubMedGoogle Scholar