Medical Management of Levodopa-Associated Motor Complications in Patients with Parkinson’s Disease
- 315 Downloads
Parkinson’s disease is a neurodegenerative disorder that affects approximately 1% of people over the age of 60 years. Levodopa is standard, and often initial, therapy for patients with this condition; however, with continued treatment and as the disease progresses, up to 80% of patients experience ‘wearing-off’ symptoms, dyskinesias and other motor complications. These levodopa-associated problems may become disabling and profoundly affect quality of life. Medications commonly used to manage these symptoms include monoamine oxidase type B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, the NMDA receptor antagonist amantadine and dopamine receptor agonists.
Agents that block MAO-B, such as rasagiline and selegiline, are used as both initial and adjunctive therapy in patients with Parkinson’s disease. These medications increase concentrations of dopamine in the brain by blocking its reuptake from the synaptic cleft, a mechanism that can slow motor decline, increase ‘on’ time and improve symptoms of Parkinson’s disease. Adverse events with these agents can include confusion, hallucination and orthostatic hypotension. MAO-B inhibition may elicit drug-drug interactions if administered with TCAs, SSRIs or serotonin-noradrenaline (norepinephrine) reuptake inhibitors. Conventional oral selegiline is associated with potentially harmful plasma concentrations of three major amfetamine metabolites, although metabolite concentrations are significantly lower with a new orally disintegrating tablet (ODT) selegeline formulation. Selegiline ODT is also absorbed more efficiently and shows less pharmacokinetic variability than conventional oral selegiline.
COMT mediates peripheral catabolism of levodopa. Therefore, agents that block COMT, such as tolcapone and entacapone, increase the elimination half-life of levodopa. Given adjunctively with levodopa, COMT inhibitors can decrease ‘off’ time and increase ‘on’ time, as well as lower the daily levodopa dose. Although more potent than entacapone, tolcapone requires monitoring for hepatotoxicity.
Amantadine is a noncompetitive NMDA receptor antagonist shown to lower dyskinesia scores and improve motor complications in patients with Parkinson’s disease when given adjunctively with levodopa.
Dopamine agonists, also used as initial and adjunctive therapy in Parkinson’s disease, improve motor response and decrease ‘off’ time purportedly through direct stimulation of dopamine receptors. Current dopamine agonists include bromocriptine, pergolide, cabergoline, lisuride, apomorphine, pramipexole, ropinirole and rotigotine. Although effective, this class of medications can be associated with cardiovascular and psychiatric adverse effects that can limit their utility.
All medications used to manage levodopa-associated motor complications in patients with Parkinson’s disease have had differing degrees of success. Although head-to-head comparisons of drugs within classes are rare, some differences have emerged related to effects on motor fluctuations, dyskinesias and on/off times, as well as to adverse effects. When choosing a drug to treat levodopa-induced complications, it is important to consider the risks and benefits of the different classes and of the specific agents within each class, given the different efficacy and safety profiles of each.
No sources of funding were used to assist in the preparation of this review. Dr Jankovic has acted as a consultant for Allergan, Eisai, Merz and Teva, and has received grants from Allergan, Amersham, Boehringer-Ingelheim, Cergene, Medtronic, Merz, Prestwick, Teva and Schwarz Pharma. Dr Stacy has acted as a consultant for and/or received honoraria and grants from GlaxoSmithKline, Novartis, Boehringer-Ingelheim, Vernalis, EMD Biosciences, Schantz and Schwarz Pharma.
- 5.Jankovic J. Pathophysiology and assessment of parkinsonian symptoms and signs. In: Pahwa R, Lyons KE, Koller WC, editors. Handbook of Parkinson’s disease. 4th ed. New York: Taylor & Francis Group, LLC, 2007: 49–75Google Scholar
- 16.Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 2005; 365(9463): 947–54PubMedCrossRefGoogle Scholar
- 32.Dostinex [package insert]. New York; Pfizer Inc, 2004Google Scholar
- 34.Horstink M, Tolosa E, Bonuccelli U, et al. Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies and the Movement Disorder Society-European Section: Pt I. Early (uncomplicated) Parkinson’s disease. Eur J Neurol 2006; 13(11): 1170–85Google Scholar
- 39.Azilect [package insert]. Kfar Saba; Teva Pharmaceutical Industries Ltd, 2006Google Scholar
- 47.Clarke A, Jankovic J. Selegiline orally disintegrating tablet in the treatment of Parkinson’s disease. Therapy 2006; 3(3): 349–56Google Scholar
- 51.Zelapar (selegiline hydrochloride) orally disintegrating tablets [package insert]. Costa Mesa (CA); Valeant Pharmaceuticals International, 2006Google Scholar
- 57.Lew M, Kricorian G. Results from a 2-year centralized tolcapone liver enzyme monitoring program [abstract no. 1035]. J Neurol Sci 2005; 238Suppl. 1: S363Google Scholar
- 59.Entacapone to tolcapone switch: multicenter double-blind, randomized, active-controlled trial in advanced Parkinson’s disease. Mov Disord 2007; 22 (1): 14-9Google Scholar
- 62.Verhagen Metman L, Del Dotto P, Blanchet PJ, et al. Blockade of glutamatergic transmission as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Amino Acids 1998; 14(1–3): 75–82Google Scholar
- 71.Lieberman A, Olanow CW, Sethi K, et al. A multicenter trial of ropinirole as adjunct treatment for Parkinson’s disease. Ropinirole Study Group. Neurology 1998; 51(4): 1057–62Google Scholar
- 84.Prescrire editorial staff. Hypersexuality due to dopaminergic drugs. Prescrire Int 2005; 14(80): 224Google Scholar
- 88.Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. The Parkinson Study Group. N Engl J Med 1999; 340 (10): 757-63Google Scholar