Selegiline has mild to moderate benefit as adjunct therapy to levodopa in advanced PD patients and is approved by the FDA in the United States for this indication. In a small double-blind placebo-controlled trial (79) of selegiline 10mg/day in PD subjects (n = 38) on stable levodopa doses, selegiline reduced daily levodopa dosage requirements (P < 0.05) and significantly improved tremor (P = 0.02) over eight weeks. Thirty subjects (selegiline n = 18, placebo n = 12) completed a 16-month follow-up (79). Both mean levodopa dosage (-133 mg/day) and dosing frequency were significantly reduced in the selegiline-treated group.
Significantly less end-of-dose akinesia was reported in double-blind crossover trials with selegiline (80,81). Golbe et al. (82) randomized 96 PD patients with motor fluctuations that could not be improved with levodopa adjustments to selegiline 10 mg/day or placebo. Mean hourly symptom control in subjects randomized to selegiline was significantly improved compared to placebo (58% vs. 26%; P < 0.01). On average, patients had one hour more on time with selegiline 10 mg/day (82). Adjunct use of selegiline reduced daily levodopa requirements by 10% to 25% (79-82). Selegiline may worsen levodopa-induced dyskinesia but once levodopa dosage adjustments are made, they are typically no worse than at baseline. Nearly 60% of subjects receiving selegiline and 30% treated with placebo reported worsened dysk-inesia within three days after starting treatment (82), with most subjects reporting improvement after reduction of the levodopa dose.
A seven-year extension of the original Palhagen study (72,83) reported 140 of the original 157 PD subjects who participated in the initial study; all were treated with levodopa and randomized to receive selegiline 10 mg/day or placebo. Selegiline slowed disease progression as measured by UPDRS total scores (P = 0.003), motor scores (P = 0.002), and ADL scores (P = 0.0002) compared with placebo. After five years, subjects on placebo had mean UPDRS total scores that were 10 points worse (P = 0.07) and were receiving 19% more levodopa (P = 0.0002) than those treated with selegiline. Wearing off fluctuations were experienced by 27% of subjects, with a trend for fluctuations to be less common (20% vs. 34%; P = 0.053) and appear later (p = 0.076) in the selegiline group over the entire seven years. Dyskinesia developed in 37% of subjects, with no significant difference in frequency (selegiline 35%, placebo 40%) or time to appearance between groups. Nausea, but not hallucinations or diarrhea, was more common in the selegiline group (24% vs. 10%, P = 0.033). This study provided evidence of long-term benefit and suggests that selegiline may reduce progression of disability in PD (83).
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