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Cochrane Database of Systematic Reviews Protocol - Intervention

Levodopa for restless legs syndrome

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the efficacy and safety of L‐dopa in comparison to placebo and other agents for patients with RLS .

Background

Clinical sleep medicine has developed rapidly in the last two decades. Especially the diagnosis and differential‐diagnosis of different subtypes of insomnia is much more sophisticated now than it was 20 years ago.

Restless legs syndrome (RLS) is a common, though often underdiagnosed, disorder with high impact on sleep. It is also called "the most common disorder you never heard of". Though already described in detail in 1945 by Ekbom (Ekbom 1945), diagnosis criteria were set up a half‐century later by the International Restless Legs Syndrome Study Group (IRLSSG, Walters 1995). The diagnostic criteria have been revised at a consensus conference held at the National Institute of Health (Allen 2003).

Essential criteria for the diagnosis of the disorder are:

  • An urge to move the legs accompanied or caused by uncomfortable and unpleasant sensations in the legs.

  • The urge to move or unpleasant sensations begin during periods of rest or inactivity such as lying or sitting.

  • The urge to move or unpleasant sensations are relieved or partially relieved by movements such as walking, stretching etc.

  • The unpleasant sensations and the urge to move only occur in the evening or at night.

Supportive, not mandatory features of the syndrome are periodic leg movements during awake (PLMW) and during sleep (PLMS). The quantification of PLMS is routinely performed in the sleep laboratory by the recording of bilateral surface electromyogram of anterior tibial muscles. PLMS also occur frequently in several other sleep disorders and may also be pres‐ent in subjects without any complaints of sleep disturbance. This applies especially to the elderly, albeit not as frequently as in patients with RLS (Allen 2003, for overview see also Hornyak 2004). Although the presence of PLMS is not specific to RLS, an elevated PLMS index (> 5 PLMS per hour of sleep) is supportive of the diagnosis of RLS (Allen 2003). The family history for the disorder is positive in 40‐60% of cases, suggesting a genetic predisposition in this group. Clinically, patients with a positive family history have an earlier onset of symptoms (before age 45) than patients without relatives afflicted with RLS. A positive response to L‐dopa also supports the diagnosis of RLS as an estimated 90% of patients report some symptom relief when treated with this agent. However, studies investigating the specifity and validity of this response have not yet been published.

Sleep disturbances are a common associated feature of the disorder and are usually the reason why patients seek medical advice (Hening 2004a). Sleep disturbances are also considered to be characteristic of the full expression of the disorder. However, because of the frequent occurrence of sleep problems in other disorders and their limited occurrence in patients with milder RLS, they are not considered as necessary for or even supportive of the diagnosis of RLS (Allen 2003). The natural course of the disorder varies greatly for milder RLS. For the patients whose symptoms start in young adult life and who eventually seek treatment, the severity and frequency of symptoms typically increases over time. Thus, the disorder is generally considered to be a chronic condition. The physical examination is usually negative for patients with idiopathic (primary) RLS. However, it is important for the clinician to look for factors that may exacerbate or trigger symptoms (secondary RLS). Aside from the established causes of secondary RLS (e.g. end‐stage renal disease, preg‐nancy and iron deficiency), there are no known physical abnormalities associated with the disorder.

Epidemiological surveys in West Europe and in the USA indicate that up to 10% of the population are afflicted with RLS. The prevalence increases with age and is in females twice as high as in males (Phillips 2000; Rothdach 2000; Ulfberg 2001; Högl 2003; Berger 2004). According to a recent survey, one third of the persons reporting RLS symptoms (i. e. 2‐3% of the population) may need medical treatment (Hening 2004a).

The condition was treated earlier with clonazepam, a benzodiazepine. In the meantime, the mainstream of therapy focuses on the therapy with L‐dopa and dopamine agonists (for a recent overview of the literature see Happe 2004; Hening 2004b). Alternative treatment options are antiepileptics like gabapentine, valproic acid and opioids (Walters 1993; Garcia‐B 2002; Eisensehr 2004; for overview see Hening 1999; Silber 2004). Though some of these substances are meanwhile used often in the treatment of RLS (e.g. opioids), the number of studies looking into substances other than dopaminergic drugs is still limited.

The etiopathophysiology of the disorder has not yet been understood. A possible dysfunction of the central nervous dopaminergic system has been generally accepted (Hening 2004; Trenkwalder 2004). An involvement of the dopaminergic system is also being assumed due to the effect that dopaminergic drugs have on the disorder (see a descriptive review of Hening 2004b). As the pathophysiology of the disorder is still unknown, there is no curative treatment for it. The treatment of RLS thus remains symptomatic.

The aim of the present review is to evaluate the therapeutic efficacy of L‐dopa treatment for the restless legs syndrome. Pharmacological treatment aims to suppress the nocturnal urge to move and the unpleasant sensations. These entail in many cases a severe curtailment of sleep and subsequently daytime fatigue, tiredness and impaired functioning. Furthermore, it is our aim to evaluate whether L‐dopa treatment suppresses periodic leg movements during sleep, which is up to now the only objective marker of the disorder. PLMS are not a pathognomonic feature of RLS as they occur also in other disorders. Therefore, PLMS can only be considered as a secondary outcome measure. Further secondary outcomes of our meta‐analysis such as parameters of daytime functioning, if studied yet, will be included.

Objectives

To evaluate the efficacy and safety of L‐dopa in comparison to placebo and other agents for patients with RLS .

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCT) testing the treatment of RLS with L‐dopa versus placebo or another drug. Parallel and cross‐over trials will be included (the second phase of cross‐over trials will be discounted as washout periods are not universally used or may not be long enough). Any formulation in which L‐dopa is available will be included: i.e. in association with carbidopa or benserazide; different types of formulations (oral, intravenous, transdermal if available, slow‐release etc.).

Types of participants

  • Adults (18 years or more)

  • Patients with RLS without comorbidity for psychiatric or organic disorders

  • Patients must fulfill diagnostic criteria for the Restless Legs Syndrome according to the International Restless Legs Syndrome Study Group (Walters 1995, Allen 2003).

Types of interventions

A therapy with L‐dopa (any dose, any regimen) will be the intervention of interest in any way of administration (oral, intravenous or transdermal). Only drugs containing L‐dopa will be considered. The minimal trial duration in terms of L‐dopa intake should be at least 7 days.

Types of outcome measures

The primary endpoint considered in this review will be:
Restlessness/unpleasant sensations as subjectively experienced by the patient. Only parameters assessed with validated instruments will be included in the analysis.

Secondary endpoints:
Efficacy:

  • PLMS index during sleep

  • Sleep quality (objective and subjective)

  • Patient satisfaction with treatment

  • Quality of life measures

Safety:

  • Adverse events occurring during treatment

  • Daytime functioning

Search methods for identification of studies

The following electronic databases will be searched:
MEDLINE 1990‐2005, EMBASE 1990‐2005, PSYCINFO 1990‐2005, CINAHL 1990‐2005, CCTR, The CCDAN controlled trials register.

The search strategy is presented for MEDLINE (OVID):

To identify RCTs the highly sensitive search strategy proposed form the Cochrane Library (Reviewers' Handbook) will be used:

#1 RANDOMIZED‐CONTROLLED‐TRIAL in PT
#2 CONTROLLED‐CLINICAL‐TRIAL in PT
#3 RANDOMIZED‐CONTROLLED‐TRIALS
#4 RANDOM‐ALLOCATION
#5 DOUBLE‐BLIND‐METHOD
#6 SINGLE‐BLIND‐METHOD
#7 #1 or #2 or #3 or #4 or #5 or #6
#8 TG=ANIMALS not (TG=HUMAN and TG=ANIMALS)
#9 #7 not #8

#10 CLINICAL‐TRIAL in PT
#11 explode CLINICAL‐TRIALS
#12 (clin* near trial*) in TI
#13 (clin* near trial*) in AB
#14 (singl* or doubl* or trebl* or tripl*) near (blind* or mask*)
#15 (#14 in TI) or (#14 in AB)
#16 PLACEBOS
#17 placebo* in TI
#18 placebo* in AB
#19 random* in TI
#20 random* in AB
#21 RESEARCH‐DESIGN
#22 #10 or #11 or #12 or #13 or #15 or #16 or #17 or #18 or #19 or #20 or #21
#23 TG=ANIMALS not (TG=HUMAN and TG=ANIMALS)
#24 #22 not #23
#25 #24 not #9

#26 TG=COMPARATIVE‐STUDY
#27 explode EVALUATION‐STUDIES
#28 FOLLOW‐UP‐STUDIES
#29 PROSPECTIVE‐STUDIES
#30 control* or prospectiv* or volunteer*
#31 (#30 in TI) or (#30 in AB)
#32 #26 or #27 or #28 or #29 or #31
#33 TG=ANIMALS not (TG=HUMAN and TG=ANIMALS)
#34 #32 not #33
#35 #34 not (#9 or #25)

#36 #9 or #25 or #35

To identify trials with l‐dopa the following steps will be made:

#37 l‐dopa in AF
#38 levodopa in AF
#39 #37 or #39

To identify trials with RLS the following strategy will be used:

#40 rls in AF
#41 restless legs syndrom* in AF
#42 #40 or #41

Finally, the searches mentioned above will be combined:

#43 #36 and #39 and 42

For other databases, this strategy (especially the phase to identify RCTs) will have to be modified to meet input recommendations.

The references of all included studies will be checked for further relevant trials.

To identify unpublished trials the first authors of randomised controlled trials will be contacted as well as the manufacturers of the agents.

Data collection and analysis

Decision to include or exclude study from review
All references fulfilling the inclusion criteria will be reviewed independently by two reviewers (MH and DR) to assess potentially relevant RCT. Any disagreement will be resolved by discussion. Subsequently, two reviewers (MH and DR) will independently assess studies for inclusion from the full text. Authorship or results will not be blinded. Any type of disagree‐ment will be resolved by discussion.

Data extraction
Data extraction will be performed using the study reports. Study authors will be contacted to provide missing data. Data will be extracted and cross‐checked by two reviewers.

Methods for statistical analysis
When possible, continuous data will be extracted and analised, using weighted mean differences. When different measurement scales are used by different studies, a standardised mean difference analysis will be performed.
For dichotomous data the odds ratios will be calculated.
By homogeneous data fixed‐, by heterogeneous (Cochrane´s Q p<0,05) data random‐effects model will be used.
Intention‐to‐treat (ITT) and per‐protocol (PP) analysis will be performed to control attrition bias.

Heterogeneity
Heterogeneity of studies will be analysed using Cochran´s Q‐ and I‐square statistic.
When possible (data not limited) and required (heterogeneity), subgroup‐analysis will be performed using the following dimensions:
A) to deal with sources of clinical heterogeneity:

  • different types of agent

  • comparator treatment (placebo or any type of substance with benefit in RLS, provided the studies fulfil the inclusion criteria )

  • duration of treatment

  • dosage of medicine

B) to deal with sources of methodological heterogeneity:

  • study type (cross‐over, parallel)

  • quality of studies (aspects see above)

Publication bias
To identify possible publication bias the funnel plots will be visually tested.