Long-term effects of pergolide in the treatment of restless legs syndrome

Methods.

Twenty-eight patients with idiopathic RLS who previously participated in a randomized, placebo-controlled, double-blind crossover study with pergolide10 were reinvestigated after 1 year in an open follow-up study. In the controlled study, patients received up to 0.75 mg pergolide 2 hours before bedtime as a single evening dose. Patients were treated with 20 mg domperidone three times daily throughout the entire study to prevent peripheral dopaminergic side effects. During the open follow-up, the dosage and administration time of pergolide were flexible. Patients were allowed to reduce the dosage to find the lowest effective dose. They also could choose to continue domperidone intake or not. Efficacy was assessed by subjective ratings and a one-night polysomnography, using the same primary end points as in the initial double-blind study (PLM index, total sleep time, subjective sleep quality) (for detailed methods, see Wetter et al.10). Statistical analysis was based on the completer population (open-label treatment with pergolide ≥1 year). Changes from baseline were analyzed by two-sample tests (Wilcoxon signed rank test). Baseline was defined as the drug-naive status before the start of the crossover trial. Similar comparisons were performed between measures at the end of the respective crossover period with pergolide treatment and follow-up to evaluate stability of favorable pergolide effects.

Results.

All 28 patients participating in the initial study (12 men, 16 women; mean age, 57.2 ± 8.9 years; range, 28 to 70) were followed-up. Complete follow-up data according to the protocol were available from 22 patients (78.6%; 9 men, 13 women; mean age, 58.2 ± 7.7 years; range, 45 to 71) ( table 1). The mean follow-up period of the 22 patients was 426.4 ± 92.3 days (range, 316 to 665). Six patients (of 28) discontinued pergolide treatment in the meantime. One 58-year-old man switched to cabergoline because of nausea and loss of efficacy 148 days after the end of the double-blind study. Two women (57 years and 65 years of age) returned to levodopa/benserazide treatment because of side effects such as nausea, vomiting, headache, and a rash at the forearm (after 3 and 30 days). A 29-year-old woman stopped pergolide after 256 days because of headache and nausea, and a 55-year-old man, taking no RLS medication at the moment, discontinued taking pergolide because of obstipation, headache, and skin changes after 13 days. A 60-year-old man stopped pergolide/domperidone treatment after 95 days because he did not want to take any medication anymore. All but one patient reported that RLS symptoms were still well controlled by pergolide just before discontinuation. The mean pergolide dosage at follow-up was lower compared with the final dosage of the initial study (0.37 ± 0.15 mg vs 0.50 ± 0.17 mg; p = 0.0152). One patient required 50/4 mg tilidine/naloxone after pergolide had been reduced from 0.75 to 0.425 mg because of side effects. Before the initial study, two patients occasionally took an additional medication during the day (50/12.5 mg levodopa/benserazide; 50/4 mg tilidine/naloxone). Follow-up analysis indicated that pergolide was still clearly significantly superior to baseline measurements in all primary and in most secondary end points. Direct comparisons between the measures at the end of the crossover period and at follow-up, however, showed a significant decreasing effect of pergolide on some outcome measures (tables 2 and 3⇓). Augmentation of restless legs symptoms developed in six (27.3%) patients. Nine of 22 follow-up completers (41%) kept taking domperidone regularly (daily dosage, 35 ± 16.6 mg; range, 15 to 60). Continuous side effects remained in 10 patients, and five patients occasionally experienced side effects (mild nausea, n = 5; congested nose, n = 2) (see table 1).

Discussion.

Subjective evaluations and sleep studies show that the beneficial effects of low-dose pergolide on sensorimotor symptoms and sleep disturbances in RLS patients persist through a median follow-up time of approximately 1 year. In 22 patients with RLS (79%), who continued open treatment after a 6-week controlled study, polysomnographic recordings confirm the significant improvement of sleep measures for up to 22 months, despite the lower mean pergolide dosage. Patients themselves reduced the dosage when they were allowed to have a flexible dosage regimen. The lower mean dose of pergolide at follow-up likely may have been responsible for the significant decreasing effect on some subjective and polysomnographic parameters when comparing follow-up and crossover measurements. However, all primary and most secondary outcome measures at follow-up were still significantly superior compared with baseline measurements. In a prior open-label study, 73% of 26 RLS patients treated with pergolide remained on the medication after a mean of 18 months, with an excellent outcome in 63%, a good outcome in 26%, and a fair outcome in 11% of the patients.7 In another extended study, 45% of 15 patients reported a complete or near-complete relief, 50% moderate control, and 5% no control of RLS symptoms after 6 to 28 months of pergolide treatment.8 In contrast to these findings, all of our patients clearly improved with pergolide, and the beneficial effect lasted for the whole follow-up period. Five (18%) of a total of 20 patients who reported side effects discontinued medication, predominantly because of nausea. Similar frequencies of intolerability have been found by others, resulting in the discontinuation of pergolide in 15.4% (4/26)7 and 25% (5/20)8 of the patients. Overall, the most frequent adverse events in our study were nausea, which was partly controlled by domperidone, and a congested nose. Insomnia frequently seen under treatment with dopamine agonists was not a clinically relevant problem. Neither were daytime fatigue or excessive daytime sleepiness.

Of our patients, 27.3% developed an augmentation of symptoms, which mainly consisted of a temporal extension of RLS symptoms in the early evening or afternoon. RLS symptoms did not involve other body parts in any patient. This time shifting was mild in all patients and not clinically relevant. Patients did not need an additional dose or an earlier application of pergolide. One patient required opioids because of intensified daytime symptoms after pergolide had been reduced and primary severe RLS symptoms had reoccurred. Although the severity of RLS symptoms during the day was rated to be somewhat higher at follow-up compared to the crossover period, it did not exceed baseline measurements. In another open study, augmentation developed as frequently (27%) as in our study, but 6 patients of 15 (40%) required an additional dose during the day to control daytime symptoms.8 Conversely, augmentation was observed less frequently (15% of the patients), but it was severe enough to discontinue pergolide treatment in one patient.7 Our study shows that augmentation seems to be no major clinical side effect of pergolide in a treatment period of at least 1 year.