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Ropinirole for RLS

Clinical bottom line

Ropinirole was effective for RLS symptoms, sleep, and periodic limb movements. After 12 weeks about 55% of patients were much, or very much improved with titrated doses of ropinirole. Compared with placebo at 12 weeks , the NNT was 5.4 (3.9 to 9.2).


References

R Allen et al. Ropinirole decreases periodic leg movements and improves sleep parameters in patients with restless legs syndrome. Sleep 2004 27: 907-914.

CH Adler et al. Ropinirole for restless legs syndrome. A placebo-controlled crossover trial. Neurology 2004 62: 1405-1407.

MT Pellecchia et al. Ropinirole as a treatment of restless legs syndrome in patients on chronic hemodialysis. Clinical Neuropharmacology 2004 27: 178-181.

C Trenkwalder et al. Ropinirole in the treatment of restless legs syndrome: results from the TREAT RLS 1 study, a 12 week randomised placebo controlled study in 10 European countries. Journal of Neurology Neurosurgery and Psychiatry 2004 75: 92-97.

AS Walters et al. Ropinirole is effective in the treatment of restless legs syndrome. TREAT RLS 2: a 12-week double-blind randomized parallel-group placebo-controlled study. Movement Disorders 2004 19: 1414-1423.

DL Bliwise et al. Randomized, double-blind, placebo-controlled, short-term trial of ropinirole in restless legs syndrome. Sleep Medicine 2005 6: 141-147.

Clinical trials

Five clinical trials compare ropinirole with placebo or levodopa, predominantly in patients without secondary cause for RLS. Three of these trials lasted 12 weeks.

Results

Details of the trials are in Table 1. The total number of patients treated with ropinirole was over 340, and most were in trials of 12 weeks duration. Quality scores on the trials were good, reflecting sponsorship by a pharmaceutical company for the larger, better quality, studies.

Table 1: Clinical trials of ropinirole

Reference
Design
Treatments and Outcomes
Patient details
Efficacy
Adverse Events
Allen et al. Sleep 2004 27: 907-914 R = 1
DB = 2
WD = 0
QS = 3
Parallel group
Duration = 12 weeks
Treatments
1 Ropinirole 0.25 to 4.0 mg daily (29)
2 Placebo (30)

Outcomes
Sleep studies, periodic limb movements, RLS symptoms
Mean age 54 years (range 30-79 years), mean duration of RLS 18 years, slightly more than half women Periodic limb movements reduced substantially with ropinirole, by more than 80%, compared with no change with placebo. Improved sleep with ropinirole but no significant difference in RLS symptom score No serious adverse events noted
AE withdrawal
1/32 ropinirole
0/33 placebo
Worsening of RLS symptoms
4/32 ropinirole
1/33 placebo
Adler et al, Neurology 2004 62: 1405-1407 R = 1
DB = 2
WD = 1
QS = 4
Crossover
Duration = four weeks
Treatments
1 Ropinirole 0.5 to 6.0 mg/day (22)
2 Placebo (22)

Outcomes
RLS rating score
The average age was 60 years (range 40 to 83 years, and most participants were women. The mean RLS score was reduced by 50% on ropinirole. RLS score below 10/40 achieved by:
9/22 ropinirole
0/22 placebo
Below 20/40:
13/22 ropinirole
5/22 placebo
No serious adverse events noted
Pellecchia et al. Clin Neuropharmacol 2004 27: 178-181 R = 2
DB = 0
WD = 1
QS = 3
Crossover
Duration = six weeks in each period
Treatments
1 Ropinirole 0.25 to 2.0 mg (11)
2 Levodopa sustained release 125-250 mg (11)

Outcomes
RLS severity
7 men 4 women, average age 56 years, with RLS duration three years, all on chronic haemodialysis Ropinirole was superior to levodopa for RLS symptoms, sleep time, and clinical global impression. Complete disappearance of RLS symptoms:
4/11 ropinirole
0/11 levodopa
None on ropinirole, one severe vomiting on levodopa, leading to discontinuation
Trenkwalder et al. J Neurol Neurosurg Psychiatry 2004 75: 92-97 R = 2
DB = 2
WD = 1
QS = 5
Parallel group
Duration = 12 weeks
Treatments
1 Ropinirole 0.25 to 4.0 mg daily (147)
2 Placebo (139)

Outcomes
Sleep, RLS symptoms, global impression
Average age 56 years (range 28-78 years), about 90% women, average duration of symptoms about 17 years Ropinirole significantly better than placebo for RLS score. Much or very much improved at 12 weeks:
78/146 ropinirole
56/137 placebo
Significantly better sleep outcomes with ropinirole
Significantly better quality of life with ropinirole
Adverse event withdrawals:
16/146 ropinirole
6/138 placebo
Lack of efficacy withdrawals:
4/146 ropinirole
11/138 placebo
Serious adverse events:
3/146 ropinirole
4/138 placebo
No reports of augmentation
Walters et al. Mov Disord 2004 19: 1414-1423 R = 2
DB = 2
WD = 1
QS = 5
Parallel group
Duration = 12 weeks
Treatments
1 Ropinirole 0.25 to 4.0 mg daily (131)
2 Placebo (136)

Outcomes
Sleep, RLS symptoms, global impression
Average age 55 years (range 29-79 years), about 60% women, average duration of symptoms about 20 years Ropinirole significantly better than placebo for RLS score. Much or very much improved at 12 weeks:
78/131 ropinirole
53/134 placebo
Significantly better sleep outcomes with ropinirole
Significantly better quality of life with ropinirole
Adverse event withdrawals:
9/131 ropinirole
11/134 placebo
Lack of efficacy withdrawals:
2/131 ropinirole
6/134 placebo
Serious adverse events:
2/131 ropinirole
5/134 placebo
No reports of augmentation
Bliwise et al. Sleep Med 2005 6: 141-147 R = 1
DB = 2
WD = 1
QS = 4
Parallel group
Duration = 2 weeks

Treatments
1 Ropinirole 0.25 to 6.0 mg daily (11)
2 Placebo (15)

Prior stabilisation on titrated ropinirole before randomisation

Outcomes
Sleep, RLS symptoms, global impression

Averegage age about 48 years, about two-thirds women, and with a mean duration of RLS of 23 years Significant worsening in leg movements on placebo. Significant inital worsening of RLS symptoms on placebo, but only at week 1 No significant difference in blind phase after open-label titration, but during titration, nausea, daytime somnolence and headache were common

Ropinirole was significantly better than placebo or L-dopa in producing good results in patients with much or very much improved results on global impression of treatment, or patients with no RLS symptoms. Four trials contributed to Figure 1, the two larger trials being over 12 weeks. For efficacy, 169/310 patients (55%) had the outcome with ropinirole compared with 109/304 (36%) with placebo or L-dopa. The relative benefit was 1.5 (1.3 to 1.8). The number needed to treat compared with placebo at about 12 weeks was 5.4 (3.8 to 9.2).

Figure 1: Much or very much improved in trials of ropinirole

All trials that measured sleep demonstrated significantly better sleep characteristics for ropinirole than for placebo or L-dopa.

Table 2 shows adverse event analysis of ropinirole and placebo, mainly at 12 weeks. There were significantly more patients experiencing at least one adverse event with ropinirole, but no difference in serious adverse events or patients discontinuing because of adverse events. There were significantly fewer discontinuations because of lack of efficacy with ropinirole.

Table 2: Adverse events with ropinirole and placebo (bold indicates number needed to treat to prevent an adverse event, NNTp)

 
Ropinirole (%)
Placebo (%)
Relative risk
(95% CI)
NNH or NNTp
(95% CI)
Patients with any AE
232/277 (84)
205/274 (75)
1.1 (1.03 to 1.2)
11 (6 to 45)
Patients with serious AE
5/342 (2)
10/338 (3)
0.6 (0.2 to 1.5)
Patients withdrawing due to AE
26/309 (9)
17/305 (6)
1.5 (0.8 to 2.7)
Patients withdrawing due to lack of efficacy
6/277 (2)
17/272 (6)
0.3 (0.1 to 0.9)
24 (13 to 140)

 

One of the trials also showed efficacy in a small number of patients with RLS secondary to uraemia.

Comment

In the whole of the RLS clinical trial literature, this is the largest data set with 700 patients, with long duration studies, of good quality, sensible outcomes, and permitting analysis of efficacy and adverse events. The results show ropinirole to be effective.

Two questions need to be answered. One is whether sleep outcomes (latency, duration, efficiency) could be combined in a more detailed pooled analysis. Because these are probably skewed, it would require access to original data. The other question concerns the natural history of RLS. Clearly, substantial numbers of patients were improving with placebo, possibly reflecting a natural tendency for the disease state to wax and wane. Comparing different interventions at different times may not be a good thing to do, therefore.