Continuous drug delivery in early- and late-stage Parkinson's disease as a strategy for avoiding dyskinesia induction and expression

TY - JOUR

T1 - Continuous drug delivery in early- and late-stage Parkinson's disease as a strategy for avoiding dyskinesia induction and expression

AU - Jenner, P.

AU - McCreary, A. C.

AU - Scheller, D. K. A.

PY - 2011/12

Y1 - 2011/12

N2 - The treatment of the motor symptoms of Parkinson's disease (PD) is dependent on the use of dopamine replacement therapy in the form of l-dopa and dopamine agonist drugs. However, the development of dyskinesia (chorea, dystonia, athetosis) can become treatment limiting. The initiation of dyskinesia involves a priming process dependent on the presence of nigral dopaminergic cell loss leading to alterations in basal ganglia function that underlie the expression of involuntary movements following the administration of each drug dose. Once established, dyskinesia is difficult to control and it is even more difficult to reverse the priming process. Dyskinesia is more commonly induced by l-dopa than by dopamine agonist drugs. This has been associated with the short duration of l-dopa causing pulsatile stimulation of postsynaptic dopamine receptors compared to the longer acting dopamine agonists that cause more continuous stimulation. As a result, the concept of continuous dopaminergic stimulation (CDS) has arisen and has come to dominate the strategy for treatment of early PD. However, CDS has flaws that have led to the general acceptance that continuous drug delivery (CDD) is key to the successful treatment of PD. Studies in both experimental models of PD and in clinical trials have shown CDD to improve efficacy, but reduce dyskinesia induction, and to reverse established involuntary movements. Two key clinical strategies currently address the concept of CDD: (1) in early-, mid- and late-stage PD, transdermal administration of rotigotine provides 24 h of drug delivery; (2) in late-stage PD, the constant intraduodenal administration of l-dopa is utilized to improve control of motor symptoms and to diminish established dyskinesia. This review examines the rationale for CDD and explores the clinical benefit of using such a strategy for the treatment of patients with PD.

AB - The treatment of the motor symptoms of Parkinson's disease (PD) is dependent on the use of dopamine replacement therapy in the form of l-dopa and dopamine agonist drugs. However, the development of dyskinesia (chorea, dystonia, athetosis) can become treatment limiting. The initiation of dyskinesia involves a priming process dependent on the presence of nigral dopaminergic cell loss leading to alterations in basal ganglia function that underlie the expression of involuntary movements following the administration of each drug dose. Once established, dyskinesia is difficult to control and it is even more difficult to reverse the priming process. Dyskinesia is more commonly induced by l-dopa than by dopamine agonist drugs. This has been associated with the short duration of l-dopa causing pulsatile stimulation of postsynaptic dopamine receptors compared to the longer acting dopamine agonists that cause more continuous stimulation. As a result, the concept of continuous dopaminergic stimulation (CDS) has arisen and has come to dominate the strategy for treatment of early PD. However, CDS has flaws that have led to the general acceptance that continuous drug delivery (CDD) is key to the successful treatment of PD. Studies in both experimental models of PD and in clinical trials have shown CDD to improve efficacy, but reduce dyskinesia induction, and to reverse established involuntary movements. Two key clinical strategies currently address the concept of CDD: (1) in early-, mid- and late-stage PD, transdermal administration of rotigotine provides 24 h of drug delivery; (2) in late-stage PD, the constant intraduodenal administration of l-dopa is utilized to improve control of motor symptoms and to diminish established dyskinesia. This review examines the rationale for CDD and explores the clinical benefit of using such a strategy for the treatment of patients with PD.

KW - CDS

KW - CDD

KW - L-dopa

KW - Rotigotine

KW - Duodopa

KW - Dyskinesia

KW - DUODENAL LEVODOPA INFUSION

KW - ROTIGOTINE TRANSDERMAL PATCH

KW - QUALITY-OF-LIFE

KW - CONTINUOUS DOPAMINERGIC STIMULATION

KW - STRIATAL SYNAPTIC PLASTICITY

KW - RANDOMIZED CONTROLLED-TRIAL

KW - DOPA-INDUCED DYSKINESIA

KW - LONG-TERM TREATMENT

KW - DOUBLE-BLIND

KW - EXTRACELLULAR DOPAMINE

U2 - 10.1007/s00702-011-0703-9

DO - 10.1007/s00702-011-0703-9

M3 - Literature review

SN - 0300-9564

VL - 118

SP - 1691

EP - 1702

JO - Journal of Neural Transmission

JF - Journal of Neural Transmission

IS - 12

M1 - N/A

ER -