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Pergolide for RLS

Clinical bottom line

Pergolide has been tested in 96 patients in four randomised trials. On the basis of limited information, it appears to be effective in reducing RLS symptoms and periodic limb movements, and improving sleep. Based on limited data from four trials significant reduction of RLS symptoms close to none occurs in about 76% of patients with pergolide and 18% with placebo, after about 4-6 weeks. The NNT at 4-6 weeks is 1.7 (1.4 to 2.1).


References

J Staedt et al. Pergolide: treatment of choice in restless legs syndrome (RLS) and nocturnal myoclonus syndrome (NMS). A double-blind randomized crossover trial of pergolide versus L-Dopa. Journal of Neural Transmission 1997 104: 461-468.

CJ Earley et al. Randomized double blind placebo controlled trial of pergolide in restless legs syndrome. Neurology 1998 51: 1599-1602.

TC Wetter et al. A randomized controlled study of pergolide in patients with restless legs syndrome. Neurology 1999 52: 944-950.

C Trenkwalder et al. Efficacy of pergolide in treatment of restless legs syndrome. The PEARLS study. Neurology 2004 62: 1391-1397.

Clinical trials

Searching found four RCTs involving pergolide, predominantly compared with placebo. Doses of pergolide were generally in the range 0.25 to 0.75 mg daily, with individual patient titration of dose to effect. Trial duration was up to six weeks, and there were two reports of longer, open label, extensions. Outcomes measured included RLS symptoms, sleep studies, and periodic limb movements.

Patients in these trials had RLS without a secondary cause, and had to fulfil strict criteria of RLS before recruitment and randomisation.

Results

Details of the trials are in Table 1. The total number of patients was not large, with 96 patients given pergolide and 102 given placebo or L-dopa.

Table 1: Clinical trial details

Reference
Design
Treatments and Outcomes
Patient details
Efficacy
Adverse Events
Staedt et al. J Neural Transm 1997 104: 461-468 R = 1
DB = 2
WD = 1
QS = 4
Crossover
Duration = two 16-day phases
Treatments
1 Pergolide 0.125 mg daily (11)
2 250 mg L-dopa + carbidopa (11)

Outcomes
Sleep studies and symptoms
Eleven patients aged 50-69 years, with duration of RLS 2-15 years, half female Therapeutic response of complete relief of night time restlessness
9/11 pergolide
1/11 dopa
No significant change in sleep
There were no serious adverse events
Nausea 9/11 pergolide
1/11 dopa
Earley et al. Neurology 1998 51: 1599-1602 R = 1
DB = 1
WD = 1
QS = 3
Parallel group
Duration = 19 days
Treatments
1 Pergolide up to 0.65 mg daily (8)
2 Placebo (8)

Outcomes
Symptoms, sleep studies
There were no differences between patients given pergolide and placebo Significant improvement on pergolide for all outcomes. No RLS symptoms
5/8 pergolide
1/8 placebo
Mean hours per day of RLS symptoms fell from about 7 hours to less than 2 hours on average with pergolide, and there was no change with placebo. The number of periodic limb movements while asleep also fell by more than 50%
Severe but not serious adverse events
4/8 pergolide
2/8 placebo
No discontinuations
Wetter et al. Neurology 1999 52: 944-950 R = 1
DB = 1
WD = 1
QS = 3
Crossover
Duration = two four-week periods
Treatments
1 Pergolide 0.25 to 0.75 mg daily (30)
2 Placebo (30)

Outcomes
Sleep studies and subjective RLS symptoms
Mean age 57 years (range 28-70), just over half women, mean duration of RLS 20 years All sleep and subjective measures significantly better with pergolide. Periodic limb movements during sleep much lower with pergolide. Extrapolation from tables suggests RLS symptoms below 3 on 0-10 scale
27/30 pergolide
8/30 placebo
No adverse events led to withdrawal with pergolide, one with placebo
Severe adverse events
5/30 pergolide
2/30 placebo
Trenkwalder et al. Neurology 2004 62: 1391-1397 R = 2
DB = 2
WD = 1
QS = 5
Parallel group
Duration = 6 weeks
Treatments
1 Pergolide 0.25 to 0.75 mg daily (47)
2 Placebo (53)

Outcomes
RLS symptoms and sleep
Mean age 56 years, and most over 51 years, somewhat more women than men, and a mean duration of RLS of more than 15 years Most sleep outcomes significantly better with pergolide than placebo. Patient global impression scores of very much or much improved:
32/47 pergolide
8/53 placebo
Periodic limb movements very much lower with pergolide than placebo (average 2 per hour versus 16 per hour)
Patients experiencing any adverse event:
31/46 pergolide
29/53 placebo

In these four trials, 73/96 patients on pergolide (76%) had an outcome of almost or complete abolition of RLS symptoms, compared with 18/102 (18%) on placebo or L-Dopa (Figure 1). The relative benefit was 4.3 (2.8 to 6.6), and the number needed to treat with pergolide for 4-6 weeks compared with placebo for one additional patient to benefit was 1.7 (1.4 to 2.1).

Figure 1: Trials of pergolide versus placebo or L-dopa. The rose-tinted symbol is the largest and best trial.

Two extension studies up to one year showed that beneficial effect of pergolide persisted, and that most patients continued to use pergolide.

Adverse events

Adverse event analysis from such a small sample cannot be trusted. Given that only 96 patients have been treated, we can be 95% sure that a serious adverse event will not occur more frequently than 1 in 30.

Comment

There is limited data, but pergolide for RLS appears to be a potentially useful therapy.