Effect of brief levodopa holidays on the short-duration response to levodopa: Evidence for tolerance to the antiparkinsonian effects

To determine whether tolerance to the antiparkinsonian actions of levodopa develops during long-term levodopa therapy, we compared the response to 2-hour levodopa infusions before and after 2- to 4-day levodopa holidays using tapping and walking speeds and tremor/dyskinesia scores as measures of response in 17 parkinsonian patients with a fluctuating response to levodopa. As expected, motor function deteriorated during the levodopa holiday, but the maximum motor tapping and walking speeds and dyskinesia scores produced by the levodopa infusion before the holiday were the same as those produced by the infusion after the holiday. Because the baseline motor function was lower after the holiday, the increment in tapping and walking speeds (ie, the difference between the baseline and the maximum response) was larger with the postholiday infusion (p < 0.01). The postholiday infusion produced a longer response than did the preholiday infusion as measured by tapping score (p = 0.047), walking speed (p = 0.02), and tremor or dyskinesia scores (p = 0.02). The prolongation of the response was greater in patients receiving larger daily doses of levodopa (r = 0.55; p = 0.03). These changes in the duration of response suggest that progressive shortening of the response to levodopa during long-term therapy is partially caused by development of tolerance to levodopa and not just by loss of dopamine storage sites. Tolerance to levodopa should be considered in establishing oral dosing regimens and in developing new strategies for drug delivery.