1

門 診 處 方 討 論 Ropinirole 用於 Restless legs syndrome (RLS) 治

療 98.9.24 黃怡君藥師

2處方 :

3

Outline

Ropinirole 的角色 ?

何謂 RLS (Restless legs syndrome) ? 如何治療 ?

Ropinirole 使用在 RLS 時用法是否合理 ?

Ropinirole 使用在 RLS 上健保是否給付 ?

其它治療 RLS 的藥物健保是否有核準 ?

4Restless legs syndrome (RLS)

Introduction Restless legs syndrome (RLS) refers to symptoms of spontaneous, continuous leg movements associated with unpleasant paresthesias. These sensations occur only at rest and are relieved by movement. The symptoms of this syndrome worsen in the evening and at night, leading to difficulty in sleeping. The abnormal feeling are typically deep seated and localized below the knees. Distribution is usually bilateral, but some asymmetry may occur and the arms can be affected in more severe cases.

5Pathogenesis  In most cases RLS is a primary idiopathic

disorder, but it also can be associated with a variety of underlying medical disorders.

Primary RLS — The cause of primary

(or idiopathic) RLS is unknown.

6Pathogenesis Secondary RLS — RLS can occur secondary to a number of disorders including ：

Iron deficiency End-stage renal disease (Uremic

polyneuropathy)- RLS is common among dialysis patients, with a reported incidence of 6 -60 ％

Diabetes mellitus Rheumatic disease Venous insufficiency Others - Multiple sclerosis, Parkinson

disease, Pregnancy 

7 Epidemiology 

Mild symptoms of RLS occur in 5-15 % of the population

RLS symptoms occurred at least twice a week and were reported as moderately or severely distressing by 2.7 %

RLS occurs among people of all ages, and the prevalence generally increases with age.

RLS also occurs in children. A biologic parent with RLS symptoms was noted for >70% of children with RLS.

8Prevalence of restless legs syndrome (RLS)

by age and sex

9 Treatment – Nonpharmacologic therapy

Iron replacement therapy Serum ferritin level ＜ 45-50 mcg/mL 給予 ferrous sulfate 325 mg tid/ da

y+ vitamin-C 100-200 mg. Ferritin levels should be checked after three to four months of therapy and then every three to six months until the serum ferritin level is greater than 50 mcg/mL and iron saturation is greater than 20 ％ .

Mental alerting activities such as video games or crossword puzzles

Avoidance of aggravating factors  ex: Caffeine, nicotine and alcohol may aggravate RLS symptom

s. Antidepressants, dopamine-blocking antiemetics (ex:metoclopramide), antihistamines may contribute to RLS symptoms.

適度的運動、熱水澡、腿部按摩、熱敷或冰敷

10Drugs used to treat restless legs syndrome

AgentInitial dose

Recommended max. daily dose

Half-life in serum Common side effects

Dopaminergic agents

Levodopa (with carbidopa or benserazide)

50 mg 200 mg hs 1.5-2 hr Nausea or vomiting, orthostatic hypotension, hallucination, augmentation of symptoms, insomnia

Pergolide* 0.025 mg 0.5 mg bid-tid 12-16 hr Same as for levodopa, plus nasal congestion and fluid retention, Cardiac valve disease

Pramipexole*(Mirapex® )

0.125 mg 1.5 mg bid-tid 8-10 hr (possibly longer with renal dysfunction)

Same as for levodopa, plus nasal congestion and fluid retention

Ropinirole*(Requip®)

0.25 mg 4 mg bid-tid 6-8 hr (possibly longer with hepatic dysfunction)

Same as for levodopa, plus nasal congestion and fluid retention

11Drugs used to treat restless legs syndrome

AgentInitial dose

Recommended maximal daily

dose Half-life in serum Common side effects

Sedative-hypnotic agents

Clonazepam 0.25 mg 2 mg hs 30-40 hr

Tolerance, sedation

Oxazepam 10 mg 40 mg hs 5-10 hr

Zaleplon 5 mg 20 mg hs 1 hr (possibly longer with hepatic dysfunction)

Zolpidem 5 mg 20 mg hs 1.6 hr (possibly longer in elderly patients or with hepatic dysfunction)

Triazolam 0.125 0.5 mg hs 2-4 hr

Antiepileptic agents 

Gabapentin 300 mg 3600 mg, tid or 1500 mg, hs

5-7 hr (possibly longer with renal dysfunction)

Sedation, dizziness, fatigue, somnolence, ataxia

12

Agent Initial dose

Recommendedmaximal daily

dose Half-life in serum Common side effects

Opiates

Propoxyphene 100-200 mg 600 mg bid-tid 6-12 hr (possibly longer with hepatic dysfunction) Sedation, pruritus,

constipation, nausea or vomiting, dry mouth, dependence

Hydrocodone 5 mg 20-30 mg bid-tid

3 hr (possibly longer with hepatic dysfunction)

Codeine 30 mg 180 mg bid-tid 2.5-3 hr (possibly longer with hepatic dysfunction)

Tramadol 50 mg 300 mg bid-tid 5-8 hr (possibly longer with hepatic or renal dysfunction)

Same as for propoxyphene and augmentation

Oxycodone 5 mg 20-30 mg, bid-tid

3 hr (possibly longer with renal dysfunction)

Sedation, pruritus, constipation, nausea or vomiting, dry mouth, dependence

Oxycodone-XR 10 mg 20-30 mg, bid-tid

12 hr (possibly longer with renal dysfunction)

Methadone* 2.5 mg 20 mg, bid-tid 16-22 hr (possibly longer with hepatic dysfunction or long-term use)

Morphine sulphate-XR

15 mg 30-45 mg, bid-tid

4 hr (possibly longer with hepatic dysfunction)

* Medication should be started at least two hours before bedtime or the anticipated onset of symptoms.

Reproduced with permission from: Earley, CJ. Restless legs syndrome. N Engl J Med 2003

13 Types of RLS

Intermittent RLS (Mild RLS ) —  That is troublesome enough when present to require treatment but that is not sufficiently frequent to require regular daily medication use.

Daily RLS (Moderate to Severe RLS ) —That is frequent and troublesome enough to require daily treatment.

Refractory RLS — Refractory RLS is defined as daily RLS treated with a dopamine agonist but with a poor response.

14

Intermittent RLS (Mild RLS ) 

Treatment options include:

Nonpharmacologic therapy

Levodopa (first)

Dopamine agonists

Low potency opioids or opioid agonists

Benzodiazepines or benzodiazepine agonists

15

Daily RLS (Moderate to severe RLS ) 

Nonpharmacologic therapy

Dopamine agonists (first)

Gabapentin

Low potency opioids or opioid agonists

Treatment options include:

16 Refractory RLS

Change to gabapentin

Change to a different dopamine agonist

Add a second agent such as gabapentin, a benzodiazepine, or an opioid

Change to a high potency opioid or tramadol

2009 UpToDate , Inc.

Treatment options include:

17Ropinirole （ Requip® ）

• A non-ergot dopamine agonist (D3＞ D2＞ D4)

• For the treatment of moderate to severe primary RLS.

• Dose titration: once daily 1-3 hrs at hs

0.25 mg for days 1 and 20.5 mg for days 3 to 71 mg for week 21.5 mg for week 32 mg for week 42.5 mg for week 53 mg for week 64 mg for week 7 Micromedex Last Modified April 21,2009

18

Ropinirole in Restless Legs Syndrome

• FDA Approval: Adult, yes; Pediatric, no

• Efficacy: Adult, Evidence favors efficacy

• Indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome

Reference: Micromedex Last Modified April 21,2009

19AASM Classification of Evidence

Recommendation Grades

Evidence Levels

Study Design

A Ｉ Large, well-designed, randomized and blinded controlled study with statistically significant conclusions on relevant variables .

B Ⅱ Smaller, well-designed, randomized and blinded controlled study with statistically significant conclusions on relevant variables

C Ⅲ Well-designed, non-randomized prospective study with control group

C Ⅳ Well-designed, large prospective study with historical controls or careful attention to confounding effects or small prospective study with control group.

C Ⅴ Small prospective study or case series without control groups .

AASM: The American Academy of Sleep Medicine

Sleep 2004;27(3):557-9

20AASM Levels of Recommendations

Term Definition

Standard This is a generally accepted patient-care strategy, which reflects a high degree of clinical certainty. The term standard generally implies the use of Level I Evidence, which directly addresses the clinical issue, or overwhelming Level II Evidence

Guideline This is a patient-care strategy, which reflects a moderate degree of clinical certainty. The term guideline implies the use of Level II Evidence or a consensus of Level III Evidence.

Option This is a patient-care strategy, which reflects uncertain clinical use. The term option implies either inconclusive or conflicting evidence or conflicting expert opinion.

Sleep 2004;27(3):557-9

21

Recommendations for treatment of RLS • Standard : Levodopa with decarboxylase inhibit

or and the dopamine agonist pergolide

• Guideline : The dopamine agonist pramipexole

• Option : The dopamine agonist ropinirole

Sleep 2004;27(3):557-9

22衛生署核准適應症

• 治療自發性帕金森氏症（ Idiopathic Parki

nson’s Disease)

• 治療原發性腿部躁動症 (Primary Restless

Legs Syndrome) 

23 全民健康保險藥品給付修正規定 97.7.1 生效• 1.3.4 帕金森氏症治療藥品 :

5. Pramipexole 及 Ropinirole 用於治療原發性腿部躁動症時需先排除腎衰竭、鐵缺乏症及多發性神經病變，且不得與 dopamine agonist 及 levodopa 併用

（ 1 ） Pramipexole 每日最大劑量 0.75mg

（ 2 ） Ropinirole 每日最大劑量為 4mg