Brief Report

Ropinirole for Restless Legs Syndrome

William Ondo, MD

Department of Neurology, Baylor College of Medicine, Houston, Texas, U.S.A.

Summary: Restless legs syndrome (RLS) is a common andunderdiagnosed condition that results in a desire to move theextremities often associated with paresthesia/dysesthesia, mo-tor restlessness, worsening of symptoms at rest with at leasttemporary relief by activity, and worsening of symptoms in theevening or night. We tested the new dopamine agonist ropin-irole in 16 patients with RLS in an open-label trial. The meandaily dose was 2.8 ± 2.3 mg (range, 0.5–12.0). The 13 patients

who completed the study reported a 58.7% improvement (p41.08 × 10−8) as judged by the abbreviated International RestlessLegs Study Group questionnaire. Three patients discontinuedthe medication secondary to adverse events (rash and nervous-ness) and other extenuating circumstances. These encouragingpreliminary results justify larger and more controlled trials ofropinirole in patients with RLS.Key Words: Restless legssyndrome—Ropinirole—Dopamine agonists—Sleep disorders.

Restless legs syndrome (RLS) is a common, poorlyunderstood condition resulting in a desire to move theextremities often associated with paresthesia/dysesthesia,motor restlessness, worsening of symptoms at rest withat least temporary relief by activity, and worsening ofsymptoms in the evening or night.1 The condition may beprimary, often demonstrating an autosomal-dominantpattern of inheritance, or secondary. Neuropathy, uremia,iron deficiency, pregnancy, and rheumatoid arthritis haveall been associated with symptoms that meet the diag-nostic criteria for RLS.2 Although some subtle clinicaldifferences may exist between primary and secondarycases, the treatment responses are usually similar.2

Currently, pharmacologic treatment of RLS varies tre-mendously. Narcotic medications, benzodiazepines, clo-nidine, carbamazepine, and gabapentin are used withvarying degrees of success. Dopaminergic medications,however, typically provide the most dramatic symptom-atic improvement. Levodopa/carbidopa, bromocriptine,and pergolide have proven efficacious against RLSsymptoms3–5; however, all three possess a significantadverse event profile (nausea, hypotension, rhinitis, andhallucinations). Levodopa can also result in rebound ex-acerbations of RLS symptoms.6

Ropinirole (Requip, SmithKline Beecham, Philadel-phia, PA, U.S.A.) is a new non-ergoline dopamine ago-nist recently approved for use in Parkinson’s disease.7 Ashort open-label trial of ropinirole was conducted to de-termine the efficacy and adverse event profile in patientswith both primary and secondary RLS.

METHODSSixteen patients were recruited from the Baylor Col-

lege of Medicine Parkinson’s Disease Center and Move-ment Disorders Clinic. All were diagnosed with RLSbased on the International Restless Legs SyndromeStudy Group (IRLSSG) criteria.1 Dosing for ropinirolewas individualized. Patients with solely nighttime symp-toms were given only evening doses, whereas patientswith symptoms throughout the day received twice a dayor three times a day dosing. Ropinirole was begun at 0.25mg/dose. Doses were doubled every week until symp-toms satisfactorily resolved or adverse events becameintolerable. Patients were allowed to reduce or discon-tinue other concurrent RLS medications if symptoms re-solved but were not allowed to increase or augment anyother medications. No changes in RLS medications wereallowed within 2 weeks of study initiation.

There is no validated scale for RLS. We used an ab-breviated questionnaire developed by the IRLSSG (Fig.1). Patients also subjectively rated responses comparedwith other medications that they had previously taken forRLS and gave global impressions.

Received May 20, 1998; revision received July 28, 1998. AcceptedJuly 31, 1998.

Address correspondence and reprint requests to William Ondo, MD,6550 Fannin Dr, Suite 1801, Houston, TX 77030, U.S.A.

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RESULTS

The data is summarized for the 13 of 16 patients whocompleted the trial in Table 1. Both primary13 and sec-ondary3 RLS patients were included. The mean age was53.7 ± 7.1 years, and duration of RLS symptoms was20.4 ± 13.0 years. The IRLSSG questionnaire scores(range, 0–24) improved from 18.6 ± 2.4 to 7.7 ± 3.5(58.7%, p4 1.08 × 10−8, two-tailed pairedt test). Tenpatients reported marked improvement and three patientsreported moderate improvement. No patient who com-pleted the study reported only mild improvement orworsening. Ten of the 13 patients who tolerated themedication felt it was the best overall treatment for theirRLS symptoms, one felt that it was equal to levodopa,one felt pergolide was superior but had worse adverseeffects, and one felt it to be equal to pramipexole.

The average total number of medications used by pa-tients for their RLS symptoms before the study was 4.2± 1.8. After beginning ropinirole, eight patients discon-

TABLE 1. Summary demographics and treatment responses

Age Sex

Symptomduration

(yrs)RLS

etiologyPrevious Rxtried for RLS

Dailydose(mg)

Durationof use(mos)

RLS score(before)

RLS score(after)

Relativerating

Changes inother Rx

Adverseevents

1 62 M 40 genetic levo, tem trazamitr, clon,chlor fluox

2.25 4 17 3 1 D/C all 0

2 58 M 3 neurop levo, carb, cod,oxaz, tram

4.0 7 19 11 1 N/A 0

3 57 F 45 primary lorhydro, temoxaz, NSAID

1.0 7 20 7 1 hydro 0

4 51 F 35 genetic levo, oxy, perg,bus

1.25 3 19 8 1* D/C all gas, sedation

5 54 F 3 neurop levo 0.5 4 18 13 1 N/A nausea6 42 F 22 genetic carb 0.5 2 12 2 1 D/C all 07 47 F 31 genetic levo, clon, lor,

fluox4.0 2 22 10 1 D/C all sedation

8 74 M 25 genetic 0 0.5 2 16 4 1 N/A 09 75 F 5 primary perg,tem,alp,

clon, amitr,fluox, levo

2.0 5 15 0 1 D/C pergtem

mild mania

10 43 F 6 primary levo, amitr, lor,dox, est,NSAID, amant,sert, traz

0.5 3 21 12 1* D/C all arm pain,GI, acne

11 58 M 17 neurop levo, perg, clon,alp, tem

2.0 3 18 10 1 D/C all fatigue

12 39 M 29 genetic levo, cod, prmclon, fluox

6.0 6 22 11 1* D/C all sedation

13 56 F 4 genetic levo,perg, carb,sert

12 3 23 9 1 D/C all 0

Avg. 53.7 — 20.4 — 4.2 meds/pt 2.8 3.9 18.6 7.7 — — —

* Relative rating was equal to another medication, Underlined, currently using at the time of study initiation; N/A, not applicable; D/C,discontinued.

Other Rx abbreviations: alp, alprazolam; amant, amantadine; amitr, amitriptyline; bus, buspirone; carb, carbamazepine; chlor, chlordiazepoxide;clon, clonazepam; cod, codeine; dox, doxepin; est, estazolam; fluox, fluoxetine; hydro, hydrocodone; hcod, hydroxycodeine; levo, levodopa/carbidopa; lor, lorazepam; meth, methadone; NSAID, any nonsteroidal anti-inflammatory agent; oxaz, oxazepam; oxy, oxycodone; perg, pergolide;prm, pramipexole; propox, propoxyphene; sert, sertraline; tem, temazepam; tram, tramadol; traz, trazadone; zolp, zolpidem.

FIG. 1. Abbreviated questionnaire developed by the InternationalRestless Legs Syndrome Study Group.

0 = non-existent, 1 = mild, 2 = moderate, 3 = severe, 4 =very severe(1) 0 1 2 3 4 Overall how would you rate the RLS dis-

comfort in your legs or arms?(2) 0 1 2 3 4 Overall how would you rate the need to

move because of the RLS symptoms?(3) 0 1 2 3 4 Overall how severe is your sleep distur-

bance from your RLS symptoms?(4) 0 1 2 3 4 Overall how severe is the impact of your

RLS symptoms on your ability to carry out your daily af-fairs, for example, carrying out a satisfactory family,home, social, or work life?

(5) 0 1 2 3 4 Overall how severe is your RLS as awhole?

(6) 0 1 2 3 4 Overall how much relief of your arm or legdiscomfort do you get from moving around? 0 = does notapply, 1 = either complete or almost complete, 2 = a mod-erate amount, 3 = a slight amount, 4 = not at all.

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Movement Disorders, Vol. 14, No. 1, 1999

tinued all other concurrent RLS medication and two pa-tients reduced their other medications. Three patientswere not taking any other medication at the onset of thestudy.

Three patients discontinued ropinirole. One 72-year-old woman with severe familial RLS, complicated by asuperimposed neuropathy, discontinued the medicationsecondary to a pan-corporeal rash and lower extremityedema. She did report ‘‘good’’ relief before this at 2mg/day. A second 42-year-old woman with familial RLSexperienced anxiety and tremor with the first dose ofropinirole. She had concurrently reduced her long-standing clonazepam dose from 1.5 mg to 1.0 mg andwas clinically thought to be experiencing benzodiazepinewithdrawal. The third woman with moderate idiopathicRLS discontinued the ropinirole secondary to moderatenausea and a severe social stress (death of her spouse).

Otherwise, adverse events were generally mild andincluded sedation,3 nausea,2 fatigue, dyspepsia, shoulderpain, acne, and hypomania.

DISCUSSION

This is the first systematic report of treating RLS withropinirole. IRLSSG questionnaire scores improved sig-nificantly. Moreover, 10 of 13 patients who tolerated themedication felt that it clearly provided the best treatmentfor their RLS symptoms at doses that were varied butgenerally smaller than those used for PD. Significantadverse events occurred in three people, although two ofthose had extenuating circumstances. Otherwise, themedication was well tolerated.

Although a variety of medications may improve RLSsymptoms, dopaminergic drugs typically provide themost consistent and robust benefit.2–6 The mechanism ofaction that results in dopaminergic improvement of RLSis unknown. Currently, there is no pathologic data, noanimal model, and relatively ambiguous physiologicaldata concerning the pathophysiology of RLS. The rela-tionship between primary and secondary RLS is alsopoorly understood. Based on clinical characteristics andtreatment responses alone, some have speculated thatRLS involves the mesencephalic dopaminergic cellgroups.2 These cells send dopaminergic tracts into thespinal cord8 and have been implicated in the suppressionof sensory impulses.9,10

Ropinirole is a synthetic dopamine agonist with rela-tively greater D3 and D4 affinity than pergolide, bromo-criptine, or dopamine.7 It has moderate opioid affinitybut does not affect any other major neurotransmitter sys-tem. After rapid and efficient oral absorption, the drug ismetabolized by CYP1A2. Elimination T1⁄2 is 6 hours and

is unaffected by renal function. The adverse events, asextrapolated from PD studies, are similar to those ofother dopaminergic drugs and typically include nausea,orthostatic hypotension, hallucinations, and sedation. Atthis time it is unclear whether any one dopamine agonistis superior to another against RLS or which properties, ifany, account for those differences.

This report is only a small, short-term, open-label trialand must therefore be interpreted with caution. Asidefrom the usual biases of an unblinded study, this samplemay represent a referral bias in that these patients werenot satisfied with their current treatment. Conversely,these patients may represent a particularly difficult-to-treat patient population because many had levodopa-induced rebound symptoms. Furthermore, the compari-son data should be especially interpreted with caution.Although all 10 patients who took both levodopa andropinirole preferred ropinirole, only five patients hadpreviously taken any other dopamine agonist. Therefore,comparison among dopamine agonists should not be at-tempted. In addition, all RLS studies suffer from the lackof any validated rating scale and are hampered by thesubjective nature of the disease. Nevertheless, themarked improvement in this small unblinded study isencouraging and may justify larger, more carefully con-trolled trials to better determine the role of ropinirole inthe treatment of RLS.

Acknowledgment:The author thanks Joseph Jankovic, MD,director of the Baylor College of Medicine Parkinson’s DiseaseCenter and Movement Disorders Clinic.

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