Effect of Long-term Therapy on the Pharmacodynamics of Levodopa: Relation to On-Off Phenomenon

doi:10.1001/archneur.1992.00530350037016

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Vol. 49 No. 11, November 1992

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Effect of Long-term Therapy on the Pharmacodynamics of Levodopa

Relation to On-Off Phenomenon

John G. Nutt, MD; William R. Woodward, PhD; Julie H. Carter, RN, MN; Stephen T. Gancher, MD

Arch Neurol. 1992;49(11):1123-1130.

Abstract

• To determine how the response to levodopa is alteredby long-term therapy, we examined the dose response to 2-hourinfusions of levodopa in three groups of parkinsonian patients:those who were previously untreated, those who exhibited stableresponses, and those who exhibited fluctuating responses tolevodopa therapy, using tapping speed as an index of bradykinesia.The baseline tapping speed was greater in the patients withstable responses than in the untreated patients, probably representinga "long-duration response" to levodopa therapy. A "short-durationresponse," indicated by an increase in tapping speed lastinghours, was observed in most patients in all groups. The onsetof the short-duration effect was more rapid and the incrementalincrease in tapping speed was twice as large in the patientswith fluctuating responses compared with the untreated patientsand patients with stable responses. The duration of the short-durationeffect was greatest in the untreated group but did not differbetween the groups with stable and fluctuating responses. Dyskinesiawas not observed in any of the de novo patients but was observedin three of 12 patients with stable responses and eight of ninepatients with fluctuating responses to levodopa therapy. Dyskinesiaappeared before or with the antiparkinsonian effects in patientswith stable responses, giving no indication of a higher thresholdfor dyskinesia in these patients compared with those with fluctuatingresponses. The plasma half-life clearance, volume of distribution,and maximum plasma concentrations of levodopa did not differamong groups. We conclude that (1) part of what has been consideredan extended short-duration response to levodopa therapy in patientswith stable responses represents instead the long-duration response;(2) a short-duration response, albeit subtle, is present inmost patients from the initiation of levodopa therapy; and (3)an increase in the magnitude of the short-duration responseand the appearance of dyskinesia cause the fluctuations to becomeclinically important, whereas a shortening of the duration ofthe response is not critical.

Author Affiliations

From the Departments of Neurology (Drs Nutt, Woodward, and Gancher and Ms Carter), Pharmacology (Dr Nutt), and Biochemistry and Molecular Biology (Dr Woodward), School of Medicine, and the Department of Adult Health and Illness, School of Nursing (Ms Carter), Oregon Health Sciences University, Portland.

Footnotes

Accepted for publication May 12, 1992.

Reprint requests to Oregon Health Science University, 3181 SamJackson Park Rd SW, L226, Portland, OR 97201-3098 (Dr Nutt).

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