Rotigotine Effects on Bladder Function in Patients with Parkinson's Disease

Abstract

Background

The objective of this study was to assess the effect of rotigotine treatment on bladder function in patients with Parkinson's disease (PD) who have urinary urgency.

Methods

in total, 20 patients with PD underwent urodynamic evaluation and completed International Prostate Symptoms questionnaires in off‐rotigotine condition and after 3 months of rotigotine patch monotherapy administration. In both sessions, clinical motor condition was evaluated with the Unified Parkinson Disease Rating Scale, Part III (motor part).

Results

Rotigotine administration significantly ameliorated the first sensation of bladder filling, the neurogenic detrusor overactive contractions threshold and bladder capacity compared with the off‐treatment condition. Moreover, the total score on the International Prostate Symptoms questionnaire revealed a decrease of filling (irritative) symptoms after rotigotine treatment compared with the off‐treatment condition.

Conclusion

The positive effects of rotigotine may be due to its balanced agonism to D1 and D2 receptors and in particular to its stimulation of D1 receptors in the anterior cingulate cortex and insula, which are known as areas involved in bladder‐inhibitory functions.

Introduction

It is well known that urinary disturbances, such as urinary urgency, are present in two‐thirds of patients with Parkinson's disease (PD).1 Urodynamic studies in patients with PD have supported clinical data demonstrating detrusor overactivity, defined as an involuntary contraction of the bladder smooth muscle (detrusor) during the storage phase.1, 2 Moreover, the frequency of urinary symptoms is statistically correlated with the severity of disease, but not with the duration of illness. Different effects of dopaminergic medication are reported in literature. Aranda and colleagues demonstrated that acute, mixed stimulation of D1 and D2 receptors by apomorphine administration reduced bladder outflow resistance3 or detrusor hyperreflexia. Conversely, acute dopaminergic stimulation by levodopa (l‐dopa) challenge reportedly worsened detrusor hyperreflexia and bladder capacity in patients with PD.4, 5 However, these data are in conflict with the clinical experience of improved bladder function in patients with PD during l‐dopa therapy, as confirmed by a study that reported a worsening in bladder function after therapy withdrawal.6 In our previous study, we compared the effects of acute versus chronic l‐dopa administration on bladder function, identified a different effect from D1 or D2 receptor activation produced by the drug, and clarified the role of the 2 subfamily receptors on micturition reflex.7 For the current study, we conducted a complete urodynamic evaluation of the effect of rotigotine, a dopamine agonist (DA) with a dopamine receptor profile well known to be distributed on D1 and D2 receptors8 and resembling chronic l‐dopa administration, on bladder function in patients with early, mild PD who complained of mild urinary urgency.

Materials and Methods

Patients

Twenty “de novo” patients (9 men and 11 women; mean age, 62.0 ± 3.2 years) who had a late diagnosis of PD (mean disease duration, 36.0 ± 5.1 months) according to Brain Bank Criteria9 were enrolled in the current study. The study was approved by our local ethics committee, and all patients provided informed consent to participate. Inclusion criteria were complaints of urinary symptoms, such as urgency and increased daytime/night time frequency defined according to the International Continence Society (ICS) standardization, and normal prostatic condition. Exclusion criteria were consumption of any drug acting on the central nervous system and/or on the lower urinary tract (LUT) and a history of urologic disorders. All patients were l‐dopa–naive and/or DA agonist‐naive. All patients provided informed consent to participate in the study.

Experimental Design

Because of their late diagnosis, only drug‐naive patients were included in the study. All participants were evaluated at the first urodynamic session in an off‐treatment condition, before the beginning of rotigotine therapy. Then, chronic rotigotine patch monotherapy was administered (median daily dose, 10 mg; range, 8–16 mg). Three months later, all patients agreed to undergo a second urodynamic session, which took place in the morning, at least 3 hours after applying the patch. All patients underwent clinical evaluations using the Unified Parkinson's Disease Rating Scale (UPDRS), Part III (motor part; 0 = normal, 108 = worst score10), which took place in both off‐treatment and on‐treatment conditions. Urodynamic evaluation, performed by 2 urologists who were blinded with regard to the assumed drugs, included a filling study (50 mL per minute water cystometry), followed by a pressure/flow study with striated pelvic floor electromyography. The procedure was conducted according to ICS11 indications.13 A 6‐French, transurethral, double‐lumen catheter was used. The following urodynamic parameters were evaluated: volume variables included first sensation of bladder filling, neurogenic detrusor overactive contractions (NDOC) threshold, bladder capacity, and post‐void residual urine (all expressed in millimeters); and pressure variables included NDOC amplitude and detrusor pressure at maximum flow (Q_max), both expressed in cm H₂O. In addition, Q_max (mL/second) was evaluated. All variables were defined according to ICS standardization.11 The International Prostate Symptoms Score (IPSS) questionnaire,12 which is widely used for quantitative, subjective evaluation of the LUT,13 was administered in the off‐treatment condition (see Table 1) and during chronic rotigotine treatment.

Table 1.

Urodynamic variables and lower urinary tract symptoms scored according to the International Prostate Symptoms Score questionnaire in patients with Parkinson's disease at baseline and after rotigotine administration

Variable	Baseline condition	Rotigotine condition
Urodynamic variables
Volume, mLa
First sensation	125 ± 48	175 ± 67*
NDOC threshold	186 ± 82	248 ± 84*
Bladder capacity	330 ± 126	390 ± 120*
Residual urine	32 ± 34	14 ± 27
Pressure, cm H2O
NDOC amplitude	24.0 ± 31.0	27.0 ± 27.0
Pdet at Qmax	15.0 ± 8.0	21.0 ± 11.0
Flow
Qmax, mL/sec	36.0 ± 14.0	36.0 ± 14.0
Lower urinary tract symptoms	Off treatment	On rotigotine
IPSS filling (max score = 15)	11.3 ± 2.0	6.2 ± 3.2
IPSS voiding (max score = 20)	4.5 ± 1.7	5.2 ± 2.3
UPDRS Part III	29.0 ± 8.1	17.0 ± 4.0
Hoehn and Yahr stage	2.5 ± 0.4	—

NDOC, neurogenic detrusor overactive contractions; Pdet, detrusor pressure; Qmax, maximum flow; IPSS, International Prostate Symptoms Score; UPDRS Part III, Unified Parkinson's Disease Rating Scale, motor part.

^aTwo‐way analysis of variance: Main factor treatment, P ˂ 0.001; post hoc *P ˂ 0.001 vs basal condition (n = 20 parkinsonian patients).

Data Analysis

For statistical analysis, separate 2‐way analyses of variance (ANOVAs) for repeated measures were used for volume and pressure variables. In both analyses, a first within‐factor “treatment” that included 2 levels (baseline condition vs. rotigotine) was used. A second ANOVA was performed using within‐factor “variables” that included 2 levels for pressure measurements and 4 levels for volume measurements. Qmax was studied using a 1‐way ANOVA with the above‐mentioned within‐factor “treatment.” Greenhouse‐Geisser correction was used when required, and the post hoc Tukey test was used when allowed. The effects of therapy withdrawal and chronic l‐dopa treatment on LUT symptoms, scored according to the IPSS questionnaire, along with scores on UPDRS Part III, were evaluated using a Friedman ANOVA with treatment as the main effect followed by a Wilcoxon post hoc test when allowed.

Results

The results are reported in Table 1. Rotigotine administration significantly ameliorated bladder volume measurements compared with baseline. The post hoc analysis showed a significant improvement (P < 0.001) in mean bladder capacity increase (50 mL), mean first desire to void increment (50 mL), and NDOC threshold increase (60 mL). No effect was observed for residual urine volume. LUT symptoms in the base condition were mild to moderate in all patients, according to IPSS scores. Total IPSS scores changed significantly during rotigotine treatment compared with baseline scores (P < 0.0005; Wilcoxon test); in particular, filling (irritative) symptoms were significantly decreased by rotigotine administration, whereas obstructive (voiding) symptoms were unchanged. The UPDRS Part III score obtained on rotigotine, as expected, was significantly lower, indicating a significant enhancement after drug administration compared with the baseline condition (Wilcoxon test) (Table 1).

Discussion

Our data demonstrate a urodynamic clinical amelioration of LUT symptoms after rotigotine treatment in a group of patients with mild PD paralleled by a significant improvement in motor symptoms. A previous study demonstrated the different roles of D1 and D2 receptors on the micturition reflex in PD and the importance of a double, balanced D1/D2 agonism for bladder function amelioration. The same authors reported that acute D2 receptor activation obtained with quinpirole worsened bladder function in normal animals, whereas the selective administration of a D1 receptor agonist (SKF 38393) did not affect any of the cystometric parameters investigated.13, 14 Accordingly, the worsening observed in patients with PD after the first acute l‐dopa administration has been related to a D2 effect, because it was counteracted by the D2 antagonist l‐sulpiride.4 Moreover, in 2006, Brusa and colleagues observed that the bladder function improvement produced by chronic l‐dopa administration was caused by a synergistic agonism on both the D1 and D2 receptor families.7 Considering the dopamine affinity (Ki) for D1 receptors (Ki = 5–10 μM) compared with that for D2 receptors (Ki = 0.5 μM),4 the authors hypothesized that, after acute l‐dopa administration in naive patients, the D2‐mediated effect would prevail on the D1‐mediated effect, whereas the reverse would be true during chronic l‐dopa administration; thus, an acute l‐dopa challenge produces a higher synaptic concentration of the drug for optimal D1 and D2 activation.15 The reported positive effect on urodynamic and IPSS variables seems to be due to the balanced action of rotigotine on the 2 dopamine receptor subfamilies, as supported by pharmacodynamics studies.8 Therefore, rotigotine stimulation of both D1 and D2 receptors resembles the larger dopamine synaptic concentrations obtained under chronic l‐dopa administration, leading to an improvement of bladder function, as observed in our patients.

According to physiological studies on voiding function that demonstrated a critical role in bladder‐inhibitory control of the anterior cingulate cortex and insula,16 which are known to have a relevant density of D1 receptors,17 it is possible to hypothesize a putative rotigotine‐mediated D1 stimulation in these sites. Conversely, a peripheral rotigotine effect can be excluded on the basis of previous studies.4, 18

Author Roles: 1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

L.B.:1A, 1B, 2B, 2C, 3A, 3B

F.P.: 2C

G.F.: 1C

V.I.: 1C

V.P.: 1B, 1C

C.I.: 1B

P.S.: 1B, 3A, 3B

E.F.A.: 1A, 2B, 2C, 3A, 3B

Disclosures

Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflict of Interest: The authors report no conflicts of interest relevant to this work.

Financial Disclosures for the previous 12 months: The authors report no sources of funding and no conflicts of interest.