Safety and Efficacy of a Transdermal Rotigotine for the Treatment of Fatigue and Quality of Life in Patients with Parkinson's Disease

Aim: To evaluate safety and efficacy of a transdermal rotigotine for the treatment of fatigue and quality of life (QOL) in patients with Parkinson's disease (PD). This was a multi-sites open-label study of 58 PD patients (male 26, female 32) who met a Japanese PD diagnosis criterion. They received a transdermal rotigotine 4.5 mg/day for 8 weeks. We added a rotigotine on the previous anti-Parkinson's drugs. Clinical signs were evaluated by Hoehn-Yahr (H-Y) stage, unified Parkin-son's disease rating scale (UPDRS), fatigue severity scale (FSS), and Euro quality of life (QOL). The scores of UPDRS improved from 35. Our data demonstrate that, in a small sample size, administration of a transdermal ro-tigotine was associated with few side effects and was modestly effective for the treatment of fatigue and QOL in patients with PD.


Introduction
Patients with Parkinson disease (PD) primarily complain motor symptoms such as akinesia, muscle rigidity or involuntary movements [1]- [3].However, they have been also affected by non-motor symptoms, autonomic dysfunction, fatigue, sleep disorders, depression, and so on [4].Non-motor symptoms occur across all stages of PD.Clinicians point that they may have a more significant impact on patients' quality of life (QOL) than motor symptoms [5] [6].Non-motor symptoms have been under-recognized, and their pathogeneses remain unclear.Dysfunction of dopaminergic and non-dopaminergic systems is considered to contribute to the development of non-motor symptoms in PD [7].Advent of drug therapy for PD can fairly control motor symptoms, but effect of dopaminergic drugs for non-motor symptoms remains poorly understood.
A transdermal patch formulation of the non-ergolinic dopamine agonist rotigotine (Neupro ® ) patch is administered transdermally resulting in stable plasma levels over 24 hours [8]- [10].In a clinical trial, RECOVER (rotigotine effects on early morning motor function and sleep in Parkinson's disease: a double-blind, randomized, placebo-controlled study), rotigotine patch demonstrated significant improvements in sleep disorders in PD patients [11].
Reviewing RECOVER and other reports, we tried to evaluate safety and efficacy of a transdermal rotigotine for the treatment of fatigue and quality of life in PD patients.

Patients and Methods
We conducted a multi-sites open-label study.58 PD patients (male 26, female 32, Table 1) who met a Japanese PD diagnosis criterion [12] were enrolled in this study.They received a transdermal rotigotine 4.5 mg/day for 8 weeks.We added a transdermal rotigotine on the previous anti-Parkinson's agents.All previous agents prescribed before the observation were required to be at stable doses for at least 8 weeks prior to baseline, and were to remain stable for the duration of the observation.
Clinical signs and severity were evaluated by Hoehn-Yahr (H-Y) stage [2], Unified Parkinson's Disease Rating Scale (UPDRS) Parts III (motor examination; in the "on" state) [13], fatigue severity scale (FSS) [14] and Euro quality of life (Euro QOL) [15].We evaluate all patients before and 8 weeks after prescribing rotigotine.Clinical evaluations were conducted regular outpatiently admission and almost all patients were on-conditions.
Efficacy variables were summarized with univariate statistics (mean ± SD), and 95% confidence intervals (CI) were calculated for changes from baseline (i.e., before and after rotigotine add-on).The ethical committee in our institution approved this study.

Results
There were no adverse side effects and all patients were fulfilled 8 weeks observation period.Concerning severity of motor symptoms, the total scores of UPDRS improved from 35.2 ± 8.0 (mean ± SD) to 31.8 ± 8.3 (Figure 1, P = 0.14), but this was not statistically significant.There was no significant improvement or worsening of the H-Y stages.Concerning severity of non-motor symptoms, the scores of FSS improved from 57.3 ± 12.7 (mean ± SD) to 50.1 ± 11.8 (Figure 2, P = 0.061) but this was not statistically significant.The scores of QOL improved from 38.1 ± 11.1 to 48.3 ± 10.0 (Figure 3, P = 0.068), but this also was not statistically significant.

Discussions
PD has been classified as "Movement Disorders" and its clinical diagnosis requires existences of tremor, bradykinesia, muscle rigidity, and loss of right reflex.Thus clinicians have tried mainly to improve these motor  weeks prescribing a transdermal rotigotine.There were no significant differences (P = 0.14) between before and after prescribing a transdermal rotigotine.weeks prescribing a transdermal rotigotine.There were no significant differences (P = 0.068), but tendencies of improvements between before and after prescribing a transdermal rotigotine.
Although we examined with a small sample size and did not optimize doses, our data demonstrate that administration of a transdermal rotigotine was associated with few side effects and was modestly effective for the treatment of fatigue and QOL in patients with PD.Although there were no significant differences (P = 0.14) between before and after motor symptoms evaluated by UPDRS, there were tendencies of improvement comparing between before and after in fatigue (P = 0.061) and in QOL (P = 0.068).This means that improvement in fatigue and QOL did not depend on improvement in motor symptoms.
Among non-motor symptoms in PD patients, fatigue was considered one of the most non-motor symptoms that were associated with signify QOL worsening [20] [21].Thus, drugs to improve fatigue in PD patients have possibility also to improve their QOL.Transdermal agents have advantage not to be affected by digestive problems that also are non-motor symptoms in PD patients.We demonstrated that a transdermal rotigotine treatment was safe and effective for fatigue in PD patients, and improved their QOL.
We prescribed rotigotine of 4.5 mg/day and this is a minimum dose of rotigotine patches in Japan.However, it is notable that this minimum dose showed effect for non-motor symptoms in PD patients.Our study also has limitation in a small number of patients.We also plan to seek optimal doses in a future study.

Figure 1 .
Figure 1.PDRS (Part III) changes from baseline after 8weeks prescribing a transdermal rotigotine.There were no significant differences (P = 0.14) between before and after prescribing a transdermal rotigotine.

Figure 2 .
Figure2.Fatigue severity scale (FSS) changes from baseline after 8 weeks prescribing a transdermal rotigotine.There were no significant differences (P = 0.061), but tendencies of improvements between before and after prescribing a transdermal rotigotine.

Figure 3 .
Figure3.Quality of life (QOL) changes from baseline after 8 weeks prescribing a transdermal rotigotine.There were no significant differences (P = 0.068), but tendencies of improvements between before and after prescribing a transdermal rotigotine.

Table 1 .
Baseline characteristic of patients.