Transdermal rotigotine for the perioperative management of restless legs syndrome

Background Immobilisation, blood loss, sleep deficiency, and (concomitant) medications during perioperative periods might lead to acute exacerbation of symptoms in patients with the restless legs syndrome (RLS). Continuous transdermal delivery of the dopamine agonist rotigotine provides stable plasma levels over 24 h and may provide RLS patients with a feasible treatment option for perioperative situations. To assess the feasibility of use of rotigotine transdermal patch for the perioperative management of moderate to severe RLS, long-term data of an open-label extension of a rotigotine dose-finding study were retrospectively reviewed. Methods The data of all 295 patients who had entered the 5-year study were screened independently by two reviewers for the occurrence of surgical interventions during the study period. The following data were included in this post-hoc analysis: patient age, sex, surgical intervention and outcome, duration of hospital stay, rotigotine maintenance dose at the time of surgery, rotigotine dose adjustment, and continuation/discontinuation of rotigotine treatment. All parameters were analysed descriptively. No pre-specified efficacy assessments (e.g. IRLS scores) were available for the perioperative period. Results During the study period, 61 surgical interventions were reported for 52 patients (median age, 63 years; 67% female); the majority of patients (85%) had one surgical intervention. The mean rotigotine maintenance dose at time of surgery was 3.1 ± 1.1 mg/24 h. For most interventions (95%), rotigotine dosing regimens were maintained during the perioperative period. Administration was temporarily suspended in one patient and permanently discontinued in another two. The majority (96%) of the patients undergoing surgery remained in the study following the perioperative period and 30 of these patients (61%) completed the 5-year study. Conclusions Although the data were obtained from a study which was not designed to assess rotigotine use in the perioperative setting, this post-hoc analysis suggests that treatment with rotigotine transdermal patch can be maintained during the perioperative period in the majority of patients and may allow for uninterrupted alleviation of RLS symptoms. Trial Registration The 5-year rotigotine extension study is registered with ClinicalTrials.gov, identifier NCT00498186.

Trial Registration: The 5-year rotigotine extension study is registered with ClinicalTrials.gov, identifier NCT00498186.

Background
Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a common neurological disorder with substantial human and economic costs [1][2][3]. The disease remains underdiagnosed and also misdiagnosed in primary care [4] which recently prompted the proposal of diagnosis and treatment algorithms for primary care physicians/general practitioners by a task force sponsored by the European RLS study group [4]. RLS patients have an urge to move their legs (and sometimes arms and other body parts) during periods of rest and inactivity; this is usually accompanied or caused by unpleasant sensations in these limbs. The general circadian pattern (worsening in the evening and at night) can change as disease severity increases, and daytime symptoms develop [5].
One of the essential diagnostic criteria for RLS is the induction or exacerbation of symptoms by rest [6]; any form of immobilisation might therefore substantially increase symptom severity. Both leg discomfort and periodic leg movements indeed significantly worsened due to immobility in RLS patients but not in healthy controls [7]. Hospital stays for surgical interventions involving bed rest and possibly forced immobilisation during the postoperative period might therefore trigger or worsen symptoms in RLS patients. Additional factors potentially contributing to this exacerbation are illness-or pain-induced sleep deprivation, iron deficiency due to perioperative blood loss, and possibly the use of certain anaesthesia and concomitant medications such as neuroleptic agents, antiemetic agents with dopamine antagonistic properties, other dopamine antagonists, opioid antagonists, and some antihistamines and antidepressants [8,9]. New onset of RLS has also been reported following surgery with spinal anaesthesia. However, as lower mean corpuscular volume and haemoglobin pre-surgery were associated with new-onset RLS after surgery in this series, it cannot be excluded that iron deficiency accounted for new onset or exacerbation of RLS in that study [10]. Worsening of RLS symptoms might result in agitated patients with involuntary limb jerks during surgery, and general restlessness and major pain during recovery with ensuing postoperative complications and poor RLS symptom control for a prolonged period following surgery [11,12].
Current recommendations for perioperative RLS management suggest maintenance of RLS medication until just before surgery and resumption after surgery at full dose [13]. When using oral dopaminergic agents with a short half life, this temporary discontinuation might worsen RLS symptoms. Resuming full-dose treatment too quickly might also be problematic with dopamine agonists which require slow titration to avoid side effects. The dopamine agonist rotigotine, an efficacious and generally well tolerated treatment for RLS and Parkinson's disease (PD) [14], might provide a suitable treatment alternative for RLS patients in the perioperative setting. Formulated in a transdermal patch, the continuous drug delivery generates stable rotigotine plasma concentrations over 24 h with once-daily application [15]. Administration of rotigotine transdermal patch may thus permit continuous alleviation of RLS symptoms in the perioperative setting. Previous studies considered rotigotine transdermal patch a feasible alternative for perioperative PD management [16,17]. Treatment was associated with good control of PD symptoms, easy switching and re-switching of regular PD medication, and a high patient acceptance [16].
In order to assess rotigotine transdermal patch for the perioperative management of RLS, long-term data of a rotigotine 5-year study were retrospectively reviewed.

Methods
Data for this post-hoc analysis were obtained from a 5-year prospective open-label study of rotigotine treatment for moderate to severe RLS (SP710, NCT00498186, [18]), which is the extension of a 6-week randomised, doubleblind, placebo-controlled rotigotine dose-finding study (SP709, NCT00243217) [19]. The study design is summarised in Figure 1. Patients eligible for participating in the dose-finding study were 18-75 years of age, had met the diagnosis of idiopathic RLS based on the four essential diagnostic criteria according to the International RLS Study Group (IRLSSG [6]), and had an IRLSSG severity rating scale (IRLS [20]) sum score ≥ 15 (= at least moderate RLS); complete inclusion/exclusion criteria are described elsewhere [19]. Study completers were given the option of long-term treatment with their optimal rotigotine dose (dose range 0.5-4 mg/24 h) provided they had no ongoing serious adverse events (AEs) suspected to be       related to their randomly assigned treatment in the preceding dose-finding study. They were excluded for severe application site reactions or noncompliance in the preceding double-blind study. During the open-label extension, administration of concomitant treatments was kept to a minimum. Visits were scheduled at monthly intervals during the first year and at 3-monthly intervals thereafter. Both studies were performed according to the Declaration of Helsinki and Good Clinical Practice, and were approved by a central institutional review board in Germany (Kommission für Ethik in der ärztlichen Forschung im Fachbereich Humanmedizin der Philipps-Universität Marburg) and in Austria (Ethikkommission der Medizinischen Universität Innsbruck). In Spain, review and approval was provided by the local ethics committees of the Hospital Universitario La Princesa, Madrid, of the Hospital de la Ribera, Alzira/Valencia, and of the USP Institut Universitari Dexeus, Barcelona. Written informed consent was obtained from all patients before participation.
The data of all 295 patients who had entered the openlabel extension (mean age, 58.3 ± 10.1 years; median, 61 years; 66% female) were screened independently by two reviewers (ES, LB) for the occurrence of surgical interventions during the study period. They reviewed all clinical study report narratives of serious AEs and other significant AEs and crosschecked the obtained information against the Council for International Organisations of Medical Sciences (CIOMS) suspect adverse reaction report forms. In case of inconsistent data, the relevant narratives and CIOMS forms were re-examined by both reviewers in order to reach an agreement about the case.
The following data were extracted for all patients with a surgical intervention during the study period: patient age, sex, surgical intervention and outcome, duration of hospital stay, rotigotine maintenance dose at the time of surgery, rotigotine dose adjustment, and continuation/discontinuation of rotigotine treatment. All parameters were analysed descriptively. No pre-specified efficacy assessments (e.g. IRLS scores) were available for the perioperative period, i.e. before and after the surgical intervention.

Surgical interventions
During the 5 year study period, 61 surgical interventions were reported for 52 patients (17.6%). These patients had a mean age of 60.4 ± 11.6 years (median, 63 years) at study entry; 67.3% were female. Table 1 lists demographics and surgery details for each patient. Forty-four patients (84.6%) had one surgical intervention; seven patients had two procedures and one patient had three interventions. The duration of patients' hospital stay ranged from 0 to 44 days. Surgeries consisted mainly of orthopaedic (45.9%), gynaecological/urological (14.8%), and cardiovascular (13.1%) procedures ( Table 2). The most frequent surgery outcome was recovered/resolved (77.1%, Figure 2). According to the very detailed case descriptions, no complications, adverse events or other surgery, RLS or medication related issues were observed. A sub-analysis of the IRLS scores at time of surgery could not be conducted in this post-hoc analysis, because data were not available; the overall study population presented with a mean IRLS score of 27.8 ± 5.9 at baseline, indicating moderate to severe RLS [21]. Although eligibility criteria of the original study stipulated the consistent use of two combined effective contraception methods (including at least one barrier method) unless sexually abstinent, one patient became pregnant and had a planned abortion. The investigator considered the abortion as not related to trial medication. The subject had been exposed to the trial medication for 607 days and was withdrawn from the study 17 days prior to the abortion.

Rotigotine dosing during the perioperative period
The rotigotine maintenance dose at the time of surgery is listed for each patient in Table 1. The mean dose was 3.1 ± 1.1 mg rotigotine/24 h (median, 3.5 mg/24 h). For the majority of interventions (n = 58, 95.1%), rotigotine dose regimens were maintained during the perioperative period. Administration was temporarily suspended in a 49-year old female patient for leg fracture surgery. Treatment was later resumed and the patient completed the study. Two patients permanently discontinued rotigotine treatment prior to surgical intervention; a Abdomen 5 Other 5 Figure 2 Reported outcome of surgical interventions.
30-year old female patient stopped rotigotine administration 17 days before her surgery due to pregnancy (study withdrawal criterion) and a 71-year old male patient withdrew in order to prepare for upcoming lipoma surgery on his right lower leg. Tumor growth had been noticed by the patient prior to the start of the study.

Study completion
In total, 50 (96.2%) of the patients undergoing surgery remained in the study following the perioperative period and 30 of these patients (61.2%) completed the 5-year study. The other 19 patients discontinued prematurely; reasons were lack of efficacy (6 patients), adverse events (4 patients, one case each of gambling, hallucinations, application site pruritus, and osteoarthritis), unsatisfactory compliance (3), major protocol violations (3), withdrawn consent (1) and others (2).

Discussion
Bed rest, forced immobilisation, pain-induced sleep deprivation, iron depletion owing to intraoperative blood loss, and medications can all exacerbate RLS symptoms during the perioperative period [9]. Additionally, the temporary discontinuation of oral RLS medication before surgery and resumption at full dose postoperatively which is currently recommended for the perioperative RLS management [13] might worsen symptoms during surgery and lead to the occurrence of side effects when re-establishing the medication postoperatively. Administration of a medication such as rotigotine transdermal patch which provides stable plasma concentrations over 24 h with once-daily application may allow an uneventful continuous management of RLS symptoms in the perioperative setting.
To investigate this hypothesis, a retrospective analysis was carried out to obtain information about the perioperative management of RLS with rotigotine transdermal patch. Data from all patients undergoing surgery during the study period were extracted from the database of a 5-year open-label rotigotine study [18]. As can be expected from a database with a median age of 61 years, surgical interventions occurred frequently [22]: nearly one fifth of all patients underwent surgery during the 5-year study period, consisting mainly of orthopaedic, gynaecological/ urological, and cardiovascular procedures. Treatment with rotigotine transdermal patch could be continued throughout the perioperative period in all but 3 of these patients without a change in rotigotine maintenance dose.
Rotigotine transdermal patch might be useful in the perioperative setting for the continuous alleviation of the usual RLS symptoms experienced by the patients. Additionally, the continuous drug delivery might counteract involuntary movements during surgery or during recovery triggered by bed rest and immobilisation, illness-or pain-induced sleep deprivation, iron depletion, (concomitant) medications, or certain anaesthetics. Several case reports have described the transient occurrence of RLS and periodic limb movements with epidural or spinal anaesthesia [10,[23][24][25][26][27][28] which might worsen the symptoms already present in RLS patients and might lead to interference with surgical procedures and a prolonged recovery time.
This investigation was a retrospective analysis and not a prospective study providing efficacy data such as IRLS values for the perioperative period. It should also be noted that the original study from which these data were obtained was not designed to assess the use of rotigotine transdermal patch in the perioperative setting. To our knowledge, no pharmacokinetic studies investigating interactions with medications commonly used during surgery have been conducted for rotigotine. The present post-hoc analysis can therefore only provide a first indication that administration of the patch can be continued satisfactorily in the majority of patients undergoing surgery and should be confirmed by additional studies.
Current guidelines recommend the use of oral opioidcontaining medications before, during, and after surgery when dopaminergic medication is suspended or slowly being re-established [13]. In case oral administration of opioid-containing medications is not possible, parenteral routes are suggested. The rotigotine transdermal patch avoids invasive routes of administration providing an alternative to patients' regular oral dopaminergic medication for the perioperative period. Although switching from different dopaminergic medications to the rotigotine patch has not been investigated systematically in RLS patients, overnight switching was effective and well tolerated in patients suffering from PD [29,30]. Switching and re-switching of regular antiparkinsonian medication to the patch was also considered feasible in perioperative PD management [16].

Conclusions
Although the data were obtained from a study which was not designed to assess rotigotine use in the perioperative setting, this post-hoc analysis suggests that treatment with rotigotine transdermal patch can be maintained during the perioperative period in the majority of patients and might thus permit uninterrupted alleviation of RLS symptoms. Rotigotine transdermal patch may be a feasible treatment alternative in perioperative situations where administration of oral treatments is limited, unavailable, or not applicable. Further prospective studies are clearly warranted to confirm this finding.
WHO has received honoraria for consultancy and for serving on scientific advisory boards, and travel support from UCB; and honoraria for consultancy and lecture fees from Teva, Novartis, GlaxoSmithKline, Boehringer Ingelheim, Orion Pharma, and Merck Serono. ES and LB are employees of UCB Pharma, Monheim, Germany; both receive UCB stock options.
Authors' contributions BH participated in study conception, data interpretation, manuscript writing, and manuscript review and critique. WHO participated in data interpretation and critical revision of the manuscript. ES and LB participated in study conception, data analysis and interpretation, and critical revision of the manuscript. All authors read and approved the final manuscript.