The levels of evidence (class I-IV) supporting the recommendations and ratings of recommendations (A-C) are defined at the end of the "Major Recommendations" field.
Drugs Acting on the Adrenoceptor
Clonidine is probably effective in reducing symptoms and sleep latency in primary restless legs syndrome (RLS) at short term (level B rating). Clonidine had several but tolerated adverse events (dry mouth, decreased cognition and libido, lightheadedness, sleepiness, headache) (level B). There is no sufficient evidence to make a recommendation about talipexole, propranolol and phenoxybenzamine, and about clonidine in secondary RLS.
Antiepileptic Drugs
Gabapentin, at 800 to 1800 mg/day can be considered effective in primary RLS (level A rating) and probably effective in secondary RLS after haemodialysis (level B). Adverse events were usually mild and reversible. Carbamazepine 100 to 300 mg and valproate slow release at 600 mg/day can be recommended as probably effective in primary RLS (level B). There is insufficient evidence to make a recommendation about topiramate and lamotrigine, and about the use of antiepileptic drugs in periodic limb movement disorder (PLMD).
Benzodiazepines/Hypnotics
Clonazepam should be considered as probably effective for improving symptoms in primary RLS when given at 1 mg before bedtime, but also probably ineffective when given at four doses throughout the day (level B rating). In PLMD, clonazepam at 0.5–2 mg/daily is probably effective in ameliorating periodic limb movements in sleep index (PLMS-I) and PLMS associated with arousals (PLMS-A) (level B) and triazolam (0.125 to 0.50 mg/day) is probably effective in ameliorating sleep efficiency and probably ineffective in reducing PLMS (level B).
Adverse events with benzodiazepines (morning sedation, memory dysfunction, daytime somnolence and muscle weakness) were usually mild, dose dependent and reversible. There is insufficient evidence to make a recommendation about alprazolam, nitrazepam, temazepam and zolpidem. Likewise no recommendation can be offered for benzodiazepines/hypnotics in secondary RLS.
Dopaminergic Agents
Levodopa
In primary RLS and at short-term follow-up, levodopa was effective in reducing symptoms of RLS and in improving sleep quality and quality of life and reducing PLMS (level A rating). Adverse events were minor but more frequent than placebo (level A). In long-term follow-up, levodopa was possibly still effective, but 30 to 70% of patients dropped out because of adverse events or lack of efficacy (level C). Augmentation probably occurred in 20 to 82% of treated patients, in a still uncertain number of them leading to treatment discontinuation. In RLS secondary to uraemia, at short-term follow-up, levodopa was probably effective in reducing symptoms, improving quality of life and reducing PLMS-I and PLMS-A (level B). In PLMD, at short-term follow-up, levodopa was probably effective in improving PLMS-I and PLMS-A (level B).
Ergot Derivatives
In primary RLS, pergolide* is established as effective at mean dosages of 0.4 to 0.55 mg/day (level A rating) and possibly effective in the long term (level C). PLMS-I and PLMS-A are also improved. Cabergoline is also effective at 0.5 to 2 mg/day (level A) and possibly effective in the long term (level C). Bromocriptine 7.5 mg can be recommended as probably effective (level B). In secondary RLS associated with chronic haemodialysis, pergolide* in short-term administration is probably ineffective at 0.25 mg/day (level B). In PLMD associated with narcolepsy, bromocriptine is probably effective (level B). Most frequent adverse events of ergot-derived dopamine agonists (nausea, headache, nasal congestion, dizziness and orthostatic hypotension) were controlled by domperidone. Augmentation was not assessed with pergolide* in class I studies. There is insufficient evidence to make a recommendation about alpha-dihydroergocryptine, lisuride and terguride.
*Note from the National Guideline Clearinghouse (NGC): On March 29, 2007, Permax (pergolide) was withdrawn from the market in the U.S. and worldwide due to safety concerns of an increased risk of cardiovascular events. See the U.S. Food and Drug Administration (FDA) Web site for more information.
Non-ergot Derivatives
In primary RLS, ropinirole at 1.5 to 4.6 mg/day has a level A rating of efficacy. Rotigotine by transdermal patch delivery is also effective in the short term (level A), and pramipexole is probably effective (level B). In RLS secondary to uraemia ropinirole is probably effective (level B). Adverse events were those common to all dopaminergic agents. Augmentation has not been well studied for any of these drugs, and has been reported by 7% of patients with ropinirole (class I evidence). There is insufficient evidence to make recommendations about the use of non-ergot derivatives in PLMD.
Opioids
For primary RLS, oxycodone at a mean dosage of 11.4 mg can be considered as probably effective in improving RLS symptoms and PLMS-I, PLMS-A and sleep efficiency on a short-term basis (level B rating). Adverse events (mild sedation and rare nocturnal respiratory disturbances on long-term use) were usually mild and reversible, problems of addiction being observed only rarely. For PLMD, short-term propoxyphene is probably ineffective in improving sleep quality and PLMS-I (level B). There is insufficient evidence to make a recommendation about morphine, tramadol, codeine and dihydrocodeine, tilidine, and methadone and about the intrathecal route of administration. There is insufficient evidence to make a recommendation about the use of opioids in secondary RLS.
Other Treatments
In primary RLS, both iron sulphate and vibration are probably ineffective (level B rating). There is insufficient evidence to make any recommendation about the use of intravenous iron dextran, magnesium oxide and amantadine. In RLS secondary to uraemia, iron dextran 1000 mg in a single intravenous dose is probably effective in the short term (<1 month) (level B). In PLMD, transdermal oestradiol is established as ineffective (level A rating) and modafinil and 1-day nocturnal haemodialysis as probably ineffective, whilst cognitive-behavioural therapy is no different than clonazepam (level B). 5-OH-tryptophan and trazodone are possibly ineffective and apomorphine and physical exercise (in myelopathy) possibly effective (level C rating).
Final Comments
For primary RLS, ropinirole given at mean dosages of 1.5 to 4.6 mg/day, and pergolide* at 0.4 to 0.55 mg/day have confirmed level A rating efficacy for relieving paraesthesia and motor restlessness. Cabergoline, levodopa and transdermal delivery rotigotine are also established as effective, the latter two so far only for short-term use (level A rating). Amongst the antiepileptic drugs, gabapentin should be considered as effective in primary RLS (level A rating).
*Note from the National Guideline Clearinghouse (NGC): On March 29, 2007, Permax (pergolide) was withdrawn from the market in the U.S. and worldwide due to safety concerns of an increased risk of cardiovascular events. See the U.S. Food and Drug Administration (FDA) Web site for more information.
For other dopaminergics (pramipexole, bromocriptine) and for valproate, carbamazepine, clonidine and oxycodone there is evidence to consider these drugs as probably effective (level B rating), whilst for clonazepam evidence for probable efficacy (at 1 mg at bedtime) and probable inefficacy (at 4 doses/day), according to dosage schedule (level B rating). Iron sulphate and vibration are probably ineffective (level B rating). In long-term use, levodopa is possibly effective (level C rating).
For RLS secondary to uraemia, levodopa, ropinirole 1.45 mg/day, gabapentin 200 to 300 mg/day and iron dextran 1000 mg intravenously (iv) are probably effective, the latter on short-term use (level B rating). For PLMD, transdermal oestradiol is ineffective (level A rating). Clonazepam and levodopa are probably effective whilst propoxyphene, triazolam, modafinil and one-night haemodialysis probably ineffective (level B rating). Bromocriptine is probably effective in PLMD associated with narcolepsy (level B). 5-OH-tryptophan and trazodone are possibly ineffective and apomorphine and physical exercise possibly effective (level C rating).
As for adverse events, these were reported as usually mild and reversible upon discontinuation of treatment in the generality of the trials. In particular the peripheral adverse events of dopaminergics were easily relieved by domperidone. For this class of drugs, augmentation represents a troublesome adverse event: even though reported particularly with levodopa, it is hard to get reliable comparative data, especially in the absence of an augmentation rating scale. Recently, concern with the ergot derivatives was raised by the discovery of severe multivalvular heart defects and constrictive pericarditis and pleuropulmonary fibrosis after long-term use in Parkinson's disease (reported with cabergoline, pergolide and bromocriptine). Daily dosages in these cases were equal or greater than 4 mg pergolide for several months. Spontaneous echocardiographic regression of valvular insufficiency along with marked clinical improvement was reported after cessation of the ergot derivatives in some case reports. It was suggested that high doses should be avoided and that patients under dopamine agonists receive a clinical cardiac assessment at 3 to 6 months intervals and if any doubt, obtain an echocardiogram. However, the cardiopulmonary fibrosis side-effects of the ergot derivatives have been described too recently for a meaningful analysis across the different compounds.
Comparison of these versus guidelines already published demonstrates minor differences in judgement, in part related to the different sets of evidence utilized. In all guidelines, dopaminergic agents come out as the best-recommended agents for the treatment of RLS. Opioids have not been here considered as established, and for iron supplementation the Task Force found only class II favourable trials (short term) or even evidence of inefficacy. Iron has been reported as more effective in low-ferritin patients. Unfortunately, still partial evidence is overall available for secondary RLS, almost all in RLS secondary to uraemia, and for PLMD. In particular, recommendations cannot be offered for RLS during pregnancy or during childhood, where quality trials are needed.
Final Level A Recommendations
For primary RLS:
- Cabergoline (0.5 to 2 mg once daily) improves RLS scores.
- Gabapentin (dosage 800 to 1800 mg/daily) reduces RLS scores and improves sleep efficiency and PLMS-I.
- Levodopa/benserazide (mean dose 159/40 mg at bedtime) improves RLS symptoms, quality of sleep, sleep latency, PLMS-I and quality of life.
- Pergolide* (mean doses 0.4 to 0.55 mg/day) is effective in improving RLS severity and ameliorating subjective quality of sleep.
*Note from the National Guideline Clearinghouse (NGC): On March 29, 2007, Permax (pergolide) was withdrawn from the market in the U.S. and worldwide due to safety concerns of an increased risk of cardiovascular events. See the U.S. Food and Drug Administration (FDA) Web site for more information.
- Ropinirole (mean doses 1.5 to 4.6 mg/day) is effective in ameliorating RLS scale scores and quality of life, and in improving sleep latency and PLMS-I/PLMS-A.
- Rotigotine by transdermal patch delivery (4.5 mg) and in short-term use improves RLS symptoms.
For PLMD:
- Transdermal oestradiol is ineffective.
Definitions:
Evidence Classification Scheme for a Therapeutic Intervention
Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:
- Randomization concealment
- Primary outcome(s) is/are clearly defined
- Exclusion/inclusion criteria are clearly defined
- Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
- Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment
Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion
Rating of Recommendations
Level A rating (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies.
Level B rating (probably effective, ineffective, or harmful) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (possibly effective, ineffective, or harmful) requires at least two convincing class III studies.
