Transdermal rotigotine for the perioperative management of restless legs syndrome

  • Birgit Högl1Email author,

    Affiliated with

    • Wolfgang H Oertel2,

      Affiliated with

      • Erwin Schollmayer3 and

        Affiliated with

        • Lars Bauer3

          Affiliated with

          BMC Neurology201212:106

          DOI: 10.1186/1471-2377-12-106

          Received: 8 December 2011

          Accepted: 31 July 2012

          Published: 25 September 2012

          Abstract

          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.

          Background

          Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a common neurological disorder with substantial human and economic costs [13]. 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, double-blind, 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.
          http://static-content.springer.com/image/art%3A10.1186%2F1471-2377-12-106/MediaObjects/12883_2011_738_Fig1_HTML.jpg
          Figure 1

          Design of the 5-year open-label extension study with rotigotine transdermal patch in restless legs syndrome (adapted from Oertel et al. [[19, 21]]). Patients completing the double-blind study had the option of long-term treatment with their optimal dose of transdermal rotigotine (0.5-4 mg/24 h) in the open-label extension.

          Written informed consent was obtained from all patients before participation.

          The data of all 295 patients who had entered the open-label 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.

          Results

          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.
          Table 1

          Characteristics of the patients included in the post-hoc analysis

          Patient

          Sex

          Agea(years)

          Surgical intervention

          Concomitant medication prior to surgery

          Surgery related concomitant medication

          Rotigotine dose at time of surgery (mg/24 h)

          Rotigotine dose following surgery (mg/24 h)

          Outcome of surgery

          10306

          Female

          60

          Bypass and tricuspidal reconstruction

          Acetylsalicylic acid 100 mg/day, fluvastatin 80 mg/day, pantoprazole sodium 40 mg/day, telmisartan 1 mg/day.

          No concomitant medications recorded

          4

          4

          recovered/resolved

          10311

          Female

          30

          Abortion

          No concomitant medications recorded

          No concomitant medications recorded

          2

          Discontinued 17 days prior to surgery

          recovered/resolved

          10402

          Female

          54

          Right knee replacement

          Zopiclone 3.75 mg/as needed

          Ibuprofen 1800 mg/day after surgery

          4

          4

          recovered/resolved with sequelae

          10404

          Female

          63

          Surgery for dislocated fracture of left distal radius

          Levothyroxine 100 μg/day

          Furosemide 20 mg/day, acemetacin 60 mg- 180 mg/day, paracetamol 4 g/day

          2

          2

          recovered/resolved

          10429

          Female

          58

          Right hip replacement

          Estradiol valerate twice weekly (unknown dose), levothyroxine sodium 50 mg/day, siccaprotect 3 drops/day (unknown dose)

          Indometacin 75 mg/day

          3

          3

          not recovered/resolved (osteoarthritis was considered to be ongoing)

          10702

          Male

          64

          Cardiac bypass surgery Right shoulder surgery (osteoarthritis) Angioplasty (internal carotid artery)

          Cardiac bypass surgery: fenofibrate 160 mg/day, serenoa repens extract 320 mg/day, Sidros 80.5 mg/day, tamsulosin 0.4 mg/day Right shoulder surgery: heparin-fraction, sodium salt (dose unknown), torasemide 10 mg/day, bisoprolol 5 mg/day, simvastatin 40 mg/day Angioplasty: no additional medication

          Cardiac bypass surgery: acetylsalicylic acid 100 mg/day, torasemide 10 mg/day, bisoprolol 5 mg/day, simvastatin 40 mg/day Right shoulder surgery: Ultracet (1tab/as needed), esomeprazole 20 mg/day, diclofenac 100 mg/day Angioplasty: no additional medication

          2

          2

          Cardiac bypass surgery: recovered/resolved Right shoulder surgery: recovered/resolved Angioplasty: recovered/resolved

          10708

          Female

          62

          Hip replacement

          Diclofenac 150 mg/day, estradiol valerate 1 mg/day

          No concomitant medications recorded

          3

          3

          recovered/resolved

          10713

          Female

          70

          Thyroid surgery Hip replacement

          Thyroid surgery: simvastatin 40 mg/day, carbamazepine 400 mg/day Hip replacement: simvastatin 40 mg/day. levothyroxine 75 mg/day

          Thyroid surgery: no concomitant medications recorded Hip replacement: no concomitant medications recorded

          4

          4

          Thyroid surgery: recovered/resolved Hip replacement: recovered/resolved

          10801

          Female

          49

          Surgery for left lower leg fracture

          Calcium with vitamin D (dose unknown), risedronate sodium 35 mg/weekly, omeprazole 40 mg/day.

          No concomitant medications recorded

          3

          3 (trial medication was temporarily suspended for the surgery and later resumed)

          recovered/resolved

          10806

          Female

          43

          Hysterectomy

          Timolol 1drop/day, domperidone 20 mg/day, acetylcysteine 600 mg/day

          No concomitant medications recorded

          4

          4

          recovered/resolved

          10906

          Female

          70

          Right knee replacement

          Lisinopril 5 mg/day, acetylsalicylic acid 100 mg/day, trospium chloride 5 mg/day, ibuprofen 600 mg/every other day.

          No concomitant medications recorded

          4

          4

          resolved with sequelae

          10907

          Female

          68

          Hallux valgus surgery

          Propranolol 50 mg/day, bisoprolol 50 mg/day, estriol 0.5 mg/biweekly

          Heparin (dose unknown), ibuprofen 1800 mg/day

          4

          4

          recovered/resolved with sequelae

          10908

          Female

          44

          Arthroscopy of right knee

          No concomitant medication reported

          Ibuprofen 600 mg/day

          2

          2

          not recovered/not resolved

          10914

          Female

          71

          Right knee replacement Left knee replacement

          Right knee replacement: bisoprolol 142.5 mg/day, ramipril 1.25 mg/day Left knee replacement: bisoprolol 142.5 mg/day, ramipril 1.25 mg/day

          Right knee replacement: no concomitant medications recorded Left knee replacement: omeprazole 20 mg/day, enoxaparin 40 mg/day, tilidine hydrochloride 200 mg/day, indometacin 75 mg/day, metamizole 20 drops/as needed, gabapentin 900 mg/day

          4

          4

          Right knee replacement: resolved with sequelae Left knee replacement: recovered/resolved with sequelae

          10915

          Female

          53

          Cholecystectomy

          Opipramol 150 mg/day, pantoprazole sodium 20 mg/day

          No concomitant medications recorded

          0.5

          0.5

          recovered/resolved

          11108

          Female

          49

          Left shoulder surgery (impingement syndrome)

          Estradiol valerat/norgestrel (administered in monthly cycle; 21 doses over 28 days)

          No concomitant medications recorded

          4

          4

          recovered/resolved

          11110

          Female

          70

          Hysterectomy

          Theophylline 400 mg/day, ibuprofen 400 mg/day, fluticasone propionate/salmeterol xinafoate (dose unknown), cromoglicate sodium/reproterol hydrochloride (dose unknown), allopurinol 300 mg/day

          No concomitant medications recorded

          2

          2

          recovered/resolved

          11112

          Female

          23

          Submandibular cyst resection

          No concomitant medications recorded

          No concomitant medications recorded

          2

          2

          recovered/resolved

          11209

          Male

          47

          Perianal abscess resection

          Diltiazem 90 mg/day, pentaerithrityl tetranitrate 80 mg/day

          Ibuprofen 1600 mg/day (discontinued because of an allergic reaction) thereafter tramadol 60 drops/day

          3

          3

          recovered/resolved

          11211

          Male

          62

          Left knee replacement

          Candesartan cilexetil (dose unknown)/day, celecoxib 100 mg/day, doxazosin mesilate (dose unknown)/day, dyazide 1tab/day, etoricoxib 60 mg/day, ibuprofen 600 mg/day, metoprolol succinate 95 mg/day, rofecoxib (dose unknown)/day

          Heparin-fraction/sodium salt 2 mL /day, metamizole sodium 2000 mg/mL/day, tramadol hydrochloride 200 mg/day

          4

          4 (after surgery), discontinued 23 days after surgery owing to rehabilitation

          recovered/resolved

          11405

          Female

          64

          Surgery for lumbar spinal cord stenosis Left shoulder surgery (frozen shoulder)

          Surgery for lumbar spinal cord stenosis: no concomitant medications recorded Left shoulder surgery: cefuroxime 1000 mg/day.

          Surgery for lumbar spinal cord stenosis: no concomitant medications recorded Left shoulder surgery: no concomitant medications recorded

          4

          4

          Surgery for lumbar spinal cord stenosis: recovered/resolved Left shoulder surgery: recovered/resolved

          11408

          Female

          63

          Vein stripping (both legs)

          Olmesartan medoxomil 20 mg/day

          Initially alfetanil, mepivacaine, midazolam, propofol (doses unknown). Thereafter ibuprofen (dose unknown)

          3

          3

          recovered/resolved

          11419

          Male

          45

          Right shoulder surgery

          No concomitant medications recorded

          Ibuprofen 400 mg/as needed

          4

          4

          recovered/resolved

          11428

          Female

          76

          Right thumb surgery (arthrosis metacarpophalangeal)

          Cyanocobalamin 1 mL/month, pantoprazole sodium 40 mg/day

          No concomitant medications recorded

          4

          4

          recovered/resolved

          11430

          Female

          60

          Hallux valgus surgery

          No concomitant medications recorded

          Diclofenac 50 mg/as needed

          2

          2

          recovered/resolved

          11501

          Male

          74

          Hip replacement

          Alprostadi cream 10 μg/day, candesartan cilexetil 4 mg/day, itraconazole solution (dose unknown)/day, nifedipine 10 mg/day

          No concomitant medications recorded

          4

          4

          recovered/resolved

          11503

          Female

          63

          Tendon repair (supraspinatus)

          Captopril 17.5 mg/day, levothyroxine sodium 50 μg/day, simvastatin 20 mg/day plus unspecified pain medication

          No concomitant medications recorded

          4

          4

          recovered/resolved with sequelae

          11601

          Female

          67

          Right knee replacement

          Acetylsalicylic acid 300 mg/day, bisoprolol (dose unknown), conjugated estrogens (dose unknown)

          Ibuprofen 800 mg/as needed, cortisone (dose unknown)/as needed

          4

          4

          recovered/resolved

          11608

          Male

          76

          Surgery for salivary gland adenoma

          Enalapril maleate 10 mg/day, amiloride hydrochlorothiazide 5 mg/day, ramipril 5 mg/day

          No concomitant medications recorded

          4

          4

          recovered/resolved with sequelae

          11609

          Male

          66

          Coronary artery disease, stent implant

          No concomitant medications recorded

          Acetylsalicylic acid 100 mg/day and blood coagulation factors 75 mg/day for 5 ½ months, thereafter asasantin 1 capsule/day; bisoprolol 5 mg/day

          4

          4

          recovered/resolved

          11612

          Male

          71

          Surgical treatment of lipoma

          No information available

          No information available

          Discontinued in order to plan for surgical treatment of the lipoma

          Discontinued

          ongoing

          11811

          Male

          64

          Hand surgery (Dupuytren’s contracture)

          Dermatologicals 1 mg/day cream, enalapril maleate 0.5 mg/day, hydrochlorothiazide and 0.5 mg/day heparin-fraction/sodium salt 2500 IU/day (day prior to surgery)

          Heparin-fraction/sodium salt 2500 IU/day, ibuprofen 600 mg/as needed

          3

          3

          recovered/resolved

          11814

          Male

          43

          Laparoscopic surgery (inguinal hernia)

          Ibuprofen 800 mg as needed, levothyroxine sodium/potassium iodide 75 μg/day

          No concomitant medications recorded

          4

          4

          recovered/resolved

          11901

          Female

          71

          Surgical elevation of bladder Radius fracture surgery

          Surgical elevation of bladder: ginkgo biloba extract 80 mg/day, acetylsalicylic acid 100 mg/day, calcium compounds 1500 mg/day, bisoprolol 5 mg/day, estrogen 0.6 mg/day, omeprazole 20 mg/day, diclofenac 75 mg/prn, hypericum perforatum 1350 mg/day, losartan 50 mg/day Radius fracture surgery: acetylsalicylic acid 100 mg/day, bisoprolol 10 mg/day, bromazepam 6 mg/as needed, calcium compounds 1500 mg/day, diclofenac 75 mg/as needed, dimethindene drops 4.5 mg/day, estrogen 0.6 mg/day, furosemide 40 mg/day, ginkgo biloba extract 80 mg/day, hypericum perforatum 1350 mg/day, losartan 50 mg/day, omeprazole 20 mg/day, prednicarbate cream (dose unknown). Prior to surgery: metamizole 1000 mg/day, tilidine 100 mg/day, enoxaparin sodium 0.4 mL/day (prophylaxis of thrombosis), cefuroxime 1.5 mg/day (inflammatory prevention), bupivacaine 10 mL, mepivacaine 40 mL (anaesthesia), clorazepate dipotassium 10 mg (tranquilizer) midazolam 6 mg (sedative)

          Surgical elevation of bladder: enoxaparin 40 mg/day, magnesium 1500 mg/day, ethinyl estradiol 20 mg/day, promethazine 25 mg/day, midazolam 3.75 mg/day, sultamicillin 1125 mg/day. Radius fracture surgery: tilidine 100 mg/day

          0.5

          0.5

          Surgical elevation of bladder: recovered/resolved Radius fracture surgery: recovered/resolved

          11902

          Female

          66

          Surgical elevation of bladder

          Esomeprazole 20 mg/day, pantoprazole 20 mg/day, methotrexate 25 mg/week, prednisolone 5 mg/day, metoprolol 25 mg/day, calcium folinate 6.35 mg/week, leflunomide 20 mg/day, nitrofurantoin 50 mg/day, vitamin C + calcium (dose unknown)

          Sulfamethoxazole (dose unknown)

          4

          4

          recovered/resolved

          12102

          Female

          59

          Repair of incisional hernia

          Diclofenac 75 mg/as needed, ibuprofen (unknown dose)/as needed, oestradiol/norethisterone acetate (unknown dose)/day, levothyroxine sodium 50 μg/day, omeprazole 20 mg/day

          Certoparia sodium 9000 units/day, thereafter novaminsulfon 1 mL/day

          3

          3

          recovered/resolved

          12103

          Female

          56

          Colon adenoma ablation

          Norethisterone acetate (dose unknown), estradiol (dose unknown), acetylsalicylic acid 750 mg/as needed

          No concomitant medications recorded

          1

          1

          recovered/resolved

          12208

          Male

          66

          Appendectomy

          Acarbose 150 mg/day, amlodipine 5 mg/day, clopidogrel sulfate 75 mg/day, fenofibrate 200 mg/day, ferrous sulfate 50 mg/day, glibenclamide 7 mg/day, lisinopril 5 mg/day, simvastatin 20 mg/day

          No concomitant medications recorded

          3

          3

          recovered/resolved

          12307

          Female

          59

          Right knee replacement Lumbar disk surgery

          Right knee replacement: diclofenac 75 mg/day (plus physiotherapy) Lumbar disk surgery: ibuprofen 600 mg/as needed, thereafter paracetamol/codeine phosphate 1560 mg/day and metamizole sodium 1500 mg/day

          Right knee replacement: diclofenac 150 mg/day, metamizole 1500 mg/day Lumbar disk surgery: oxycodone/naloxone 30 mg/day, tilidine drops (dose unknown)/as needed, fentanyl patch 50 μg/week

          4

          4

          Right knee replacement: recovered/resolved with sequelae Lumbar disk surgery: recovering/resolving

          12315

          Male

          46

          Meniscus surgery

          Acetylsalicylic acid 100 mg/day.

          No concomitant medications recorded

          3

          3

          recovered/resolved

          12401

          Male

          66

          Prostate resection

          Bisoprolol hemifumarate 5 mg/day, flecainide acetate 100 mg/day, lansoprazole 15 mg/day, valsartan drops 160 mg/day

          No concomitant medications recorded, no chemotherapy, no tumor markers

          4

          4

          recovered/resolved

          12603

          Female

          63

          Vein stripping (both legs)

          Biotin 2.5 mg/week, calcium 500 mg/day, ergocalciferol 0.025 mg/day, estradiol (dose unknown), zinc 25 mg/week, unspecified other urologicals, including antispasmodics. Prior to surgery: 40 mg/day heparin fraction/sodium salt for the prevention of thrombosis

          No concomitant medications recorded, compression stockings recorded as therapy

          2

          2

          recovered/resolved

          12606

          Male

          63

          Vein stripping (right leg)

          Acetylsalicylic acid 300 mg/day, allopurinol 300 mg/day, bisoprolol 5 mg/day, insulin 48 IU/day, metformin 850 mg/day, ramipril 1 mg/day

          No concomitant medications recorded

          3

          3

          recovered/resolved

          12701

          Male

          70

          Pelvic bypass surgery

          Acetylsalicylic acid 200 mg/day, nafti-ratiopharm retard 400 mg/day

          No concomitant medications recorded

          3

          3

          recovered/resolved with sequelae

          13001

          Female

          72

          Surgery for left orbital fracture

          Mesalazine 1500 mg/day, amlodipine 5 mg/day

          No concomitant medications recorded

          4

          4

          recovered/resolved

          13002

          Female

          49

          Hysterectomy

          No concomitant medications recorded

          No concomitant medications recorded

          4

          4

          recovered/resolved

          13013

          Female

          75

          Hip replacement (left) Hip replacement (right)

          Hip replacement (left) and hip replacement (right):valsartan/hydrochlorothiazide (dose unknown), diclofenac 100 mg/as needed and 75 mg/as needed, diclofenac potassium 50 mg/as needed, lercanidipine 10 mg/day, metoprolol (dose unknown)

          Hip replacement (left) and hip replacement (right): no concomitant medications recorded

          0.5

          0.5

          Hip replacement (left): recovered/resolved Hip replacement (right): recovered/resolved

          13102

          Female

          63

          Vertebral fusion (spondylolisthesis) Vertebral fusion (spondylolisthesis)

          Both surgeries: lercanidipine 10 mg/day, pravastatin sodium 40 mg/day, ibuprofen 400 mg/as needed.

          Both surgeries: no concomitant medications recorded

          4

          4

          Both surgeries: recovered/resolved

          14007

          Male

          66

          Osteotomy of right distal tibia

          Heparin-fraction/sodium salt 40 mg/day,

          Heparin-fraction/sodium salt 40 mg/day, naproxen 1000 mg/day, pantoprazole 20 mg/day

          3

          3

          recovered/resolved

          17005

          Female

          47

          Hysterectomy

          Ibuprofen 600 mg as needed

          No concomitant medications recorded

          3

          3

          recovered/resolved

          17007

          Female

          71

          Hip prosthesis replacement

          Chondroitin sulfate sodium 800 mg/day, glucosamine sulfate 1500 mg/day, ibuprofen 400 mg/as needed, paracetamol 600 mg/as needed

          Acetylsalicylic acid 300 mg/day, enoxaparin 40 mg/day, alendronate sodium 70 mg/week, calcium 500 mg/day, ciprofloxacin 1500 mg/day, paracetamol 4 g/day, metamizole 150 mg/day, omeprazole 20 mg/day, thiamine nitrate/pyridoxine hydrochloride, clonazepam 2.5 mg/day (for RLS, immediately after surgery)

          4

          4

          recovering/resolving

          17301

          Male

          71

          Bladder resection

          Pentoxifylline 800 mg/day, tamsulosin 0.4 mg/day

          No concomitant medications recorded

          4

          4

          recovered/resolved

          a at start of open-label extension period.

          Table 2

          Surgical interventions during the 5-year rotigotine study

          Surgical intervention

          Number

          Orthopaedics

          28

          Gynaecology/Urology

          9

          Cardiovascular

          8

          Trauma

          6

          Abdomen

          5

          Other

          5

          http://static-content.springer.com/image/art%3A10.1186%2F1471-2377-12-106/MediaObjects/12883_2011_738_Fig2_HTML.jpg
          Figure 2

          Reported outcome of surgical interventions.

          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 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, 2328] 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 opioid-containing 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.

          Declarations

          Acknowledgements

          Both the 5-year study and the current analysis which used data from this study were sponsored by UCB Pharma, Monheim, Germany. The sponsor was involved in the design of the post-hoc study, analysis and interpretation of the data, manuscript writing, and in the decision to submit the paper for publication. The authors wish to thank E. Grosselindemann (Brett Medical Writing, Bibra Lake, Australia) and B. Brett (Brett Medical Writing, Pulheim, Germany) for writing and editorial assistance which was contracted by UCB Pharma, Monheim, Germany.

          Authors’ Affiliations

          (1)
          Department of Neurology, Innsbruck Medical University
          (2)
          Department of Neurology, Philipps University
          (3)
          UCB Biosciences GmbH

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          31. Pre-publication history

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          Copyright

          © Högl et al.; licensee BioMed Central Ltd. 2012

          This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.