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 levo dopa develops during longterm levodopa therapy, we compared the respon se 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 fluctuatin g response to levodopa. As expected, motor function deteriorated durin g the levodopa holiday, but the maximum motor tapping and walking spee ds and dyskinesia scores produced by the levodopa infusion before the holiday were the same as those produced by the infusion after the holi day. Because the baseline motor function was lower after the holiday, the increment in tapping and walking speeds tie, the difference betwee n the baseline and the maximum response) was larger with the postholid ay infusion (p < 0.01). The postholiday infusion produced a longer res ponse 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 re ceiving larger daily doses of levodopa (r = 0.55; p = 0.03). These cha nges in the duration of response suggest that progressive shortening o f the response to levodopa during long-term therapy is partially cause d by development of tolerance to levodopa and not just by loss of dopa mine storage sites. Tolerance to levodopa should be considered in esta blishing oral dosing regimens and in developing new strategies for dru g delivery.