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Restless legs: impact and treatment update

RLS impact
Results
Trials of treatment
Comment

Bandolier has been keeping a quiet eye on restless legs syndrome (RLS). It is common (Bandolier 118), and though Bandolier has looked previously at trials of pergolide (Bandolier 67), those were very small with fewer than 60 patients in three trials. Because RLS is common, and because there are limited therapies available, any pharmaceutical company worth its salt would be looking for the possibility of significant potential sales with an effective drug. This may be happening, because we now have newer, larger, and better trials, and large surveys of the impact of RLS on patients, all funded by pharmaceutical interest in this area.

RLS impact

A large primary care survey of RLS addressed this question [1]. It was conducted in France, Germany, Spain, UK and USA, involved 182 primary care doctors and 23,052 patients. Patients who visited their doctor for any reason over a two week period were asked to complete a screening questionnaire based on standard diagnostic criteria. A presumptive diagnosis required positive answers to four diagnostic questions (summarised in the Box).




Diagnostic questions for RLS

  1. Do you have, or have you sometimes experienced, recurrent, uncomfortable feelings or sensations in your legs while sitting or lying down?
  2. Do you have, or have you sometimes experienced, a recurrent need or urge to move your legs while sitting or lying down?
  3. When present, do these feelings or movements improve or go away when you get up and walk around, for as long as you are walking?
  4. Are these uncomfortable feelings, or this urge to move, worse in the evening or at night, compared with the morning?
  5. During the last 12 months, have these uncomfortable feelings or sensations in your legs, or the need to move your legs while sitting or lying down, happened to you on average for one or more nights/days per week?



Those with a presumptive diagnosis and with at least weekly frequency of restless legs were then asked additional questions about diagnosis, demographics, lifestyle, frequency, symptoms, and consultation and treatment.

Results

Prevalence of various degrees of RLS in different countries and overall is shown in Table 1. RLS sufferers (defined as having symptoms at least twice weekly and some or high negative impact of symptoms of quality of life) were 3.4% of the population.




Table 1: RLS prevalence by country



Percent of population with symptoms
Country
Sample size
Any frequency
At least weekly
RLS sufferers
France
4808
7.4
5
2.1
Germany
6723
11.4
7.9
3.7
Spain
5752
5.5
3.6
1.9
UK
2114
14.2
11.3
5.6
USA
3655
13.3
11.3
5.8
All
23052
9.6
7.1
3.4



Symptoms of restless RLS considered most troublesome by RLS sufferers included sleep-related symptoms, uncomfortable feelings in the legs, and pain (Figure 1). Many RLS sufferers took a long time to get to sleep (Figure 2), or were woken many times in the night (Figure 3). RLS sufferers were more likely than responders with at least weekly occurrence of restless legs to have a diagnosis of depression, insomnia, arthritis, nocturnal cramps, or neuropathy.




Figure 1: Symptoms of RLS sufferers







Figure 2: Time to sleep of RLS sufferers







Figure 3: Times RLS sufferers woken at night






Two-thirds of RLS sufferers had consulted a doctor about their symptoms in the previous year. Overall half of sufferers had been referred to a specialist, though with large differences between countries, as low as 17% in the UK and has high as 73% in France (Figure 4).




Figure 4: RLS sufferers referred to specialist






Trials of treatment

Three trials have been reported in 2000-2004 (Table 2). All were randomised, double-blind trials of high quality over six to 12 weeks duration. Significant benefit over placebo was reported for gabapentin, ropinirole, and pergolide. Using outcome of mild RLS score, or much or very much improved by end of trial, the percentage benefiting and NNTs are shown in Table 3. Given the limited amount of information, and a possible duration effect in trials, not too much should be made about any differences between treatments.




Table 2: Recent randomised trials in RLS



Reference Study Methods Main results
Garcia-Borreguero et al. Neurology 2002 59: 1573-1579.
QS = 5
Randomised, double-blind, double-dummy, crossover comparing gabapentin with placebo for 6 weeks
24 subjects meeting International RLS criteria
Gabapentin started at daily dose of 600 mg, with titration up to 2,400 mg. Identical protocol for placebo.
Outcomes RLS rating, patient global evaluation, sleep, adverse events
Mean end gabapentin dose 1,800 mg daily
RLS rating mild 16/24 gabapentin; 8/24 placebo
Patient global, sleep significantly better with gabapentin
Adverse events higher with gabapentin, but no adverse event withdrawals
Trenkwalder et al. J Neurol Neurosurg Psychiatry 2004 75: 92-97.
QS = 5
Randomised, double-blind, parallel-group comparison of ropinarole with placebo for 12 weeks
286 subjects meeting International RLS criteria
Ropinirole started at 0.25 mg/day, and titrated upwards over six weeks to maximum of 4.0 mg/day. Identical protocol for placebo.
Outcomes RLS rating, patient global evaluation, sleep, quality of life, adverse events
Mean end ropinirole dose at 12 weeks 1.9 mg/day
RLS score lower than placebo at 12 weeks
At 1 week, much or very much improved in 40/146 with ropinirole and 18/137 with placebo
At 12 weeks, much or very much improved in 78/146 with ropinirole and 56/137 with placebo
Sleep measures better with ropinirole, but no difference for SF-36 scores
Adverse events more common with ropinirole
Trenkwalder et al. Neurology 2004 62: 1391-1397.
QS = 5
Randomised, double-blind, parallel-group comparison of pergolide with placebo for 6 weeks
100 subjects meeting International RLS criteria
Pergolide started at 0.05 mg/day and increased to 0.25 mg/day by day 8, with subsequent adjustments to 0.75 mg/day. Identical protocol for placebo.
Outcomes patient global evaluation, sleep measures
Mean end pergolide dose was 0.4 mg/day
Much or very much improved at 6 weeks in 32/47 patients on pergolide and 8/53 on placebo
Sleep significantly improved with pergolide
AE in 31/46 pergolide, 29/53 placebo





Table 3: NNTs for RLS treatments



Percent improved with
Treatment
N
Weeks
Treatment
Placebo
NNT
(95% CI)
Gabapentin
24
6
67
33
3.0 (1.7 to 15)
Ropinirole
286
12
53
41
8.0 (4.2 to 99)
Pergolide
100
6
68
15
1.9 (1.4 to 2.7)



Comment

What we have here is another step forward. The prevalence is the same as the large survey reported in Bandolier 118. The efficacy of pergolide in the large study is roughly the same as that reported in three tiny trials in Bandolier 67.

So we have a small step forward in our knowledge, though the three drugs may not be licensed for RLS in many jurisdictions. We can confirm that RLS is common, significantly affects about 1 in 30 people, and that there are treatments that work for some at the cost of some adverse effects.

The latest version of diagnostic questions for restless legs is in Table 4 [2].




Table 4: Updated diagnostic questions



1
Do you have unpleasant sensations in your legs combined with an urge or need to move your legs?
Yes or No
2
Do these feelings occur mainly or only at rest and do they improve with movement?
Yes or No
3
Are these feelings worse in the evening or night than in the morning?
Yes or No
4
How often do these feelings occur?

Less than one time per year

At least one time a year but less than one time a month

One time per month

2-4 times per month

2-3 times per week

4-5 times per week

6-7 times per week

A positive diagnosis requires the respondent to answer Yes to the first three questions. The fourth question provides an indication of the severity of the condition.



Reference:

  1. W Hening et al. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Medicine 2004 5: 237-246.
  2. RP Allen et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Medicine 2003 4: 101-119.

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