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Restless leg syndrome

Originally defined by a Swedish neurologist in the 1940s, restless leg syndrome is now thought to affect up to 15% of the population, particularly older people. Four basic elements must be present to make the diagnosis:

  1. A desire to move the limbs, often associated with paresthesia or dysaesthesia
  2. Symptoms exacerbated by rest and relieved by activity
  3. Motor restlessness
  4. Nocturnal worsening of the symptoms

What helps? L-dopa and benzodiazepines have been tried, but there are now three high-quality randomised studies of pergolide (a dopamine receptor agonist) which show it to be highly effective. Details of the studies are shown in the Table. All of the studies were well-designed and highly detailed in the outcomes they examined, and all of them allowed a period of dose-escalation with both pergolide and comparator with drug formulations of identical appearance.

Table: Randomised, double-blind trials of pergolide in restless legs syndrome
Reference Design Pergolide Comparator Main outcomes Main results Adverse effects
Staedt et al, 1997 Randomised, double-blind crossover study in 11 patients, two 16-day phases 0.125 mg at night increased to 0.250 mg if needed (mean final dose 0.159 mg) L-dopa 250 to 500 mg (final dose 363 mg) Patient outcomes, poly-somnography 11/11 complete or nearly complete resolution with pergolide, 1/11 on L-dopa Significant improvement in sleep and reduced movement times from 165 minutes at baseline to 35 minutes on pergolide Initial nausea with pergolide successfully treated with domperidone 60 mg. No discontinuations because of adverse effects.
Earley et al, 1998 Randomised, double-blind parallel group study in 16 patients over 18 days Self-adjusted schedule, 0.05 to 0.65 mg a day (final median dose 0.35 mg) Placebo Poly-somnography, sleep measures, periodic limb movements of sleep Significant reduction in sleep limb movements from 49 to 14 per hour on pergolide. Improved sleep and hours a day of restless legs. No change with placebo. 5/8 complete resolutions on pergolide Mild adverse effects with pergolide and placebo. No discontinuations because of adverse effects.
Wetter et al, 1999 Randomised, double-blind crossover study in 28 patients, two 6-week phases Up to 0.75 mg titrated up from starting dose of 0.05 mg (final mean dose 0.51 mg) Placebo Poly-somnography, sleep measures, periodic limb movements of sleep, sleep diaries, patient and physician outcomes Significant improvement in all sleep measures. Periodic limb movements reduced from 55 per hour on placebo to 5 per hour on pergolide. Patient severity of restless leg average below 1 on scale of 10. Nausea, headache and rhinitis were main adverse effects on pergolide. Headache, abdominal pain, constipation and nausea with placebo. 1 patient withdrew on placebo because of abdominal pain.

Göttingen [1]


This study showed a dramatic drop in night time restless leg movement time from a pre-treatment control mean of 165 minutes to 35 minutes with pergolide but a non-significant drop to 91 minutes with L-dopa. All 11 patients had complete (9) or almost complete (2) relief with pergolide as against only one of 11 with placebo.

Baltimore [2]


Compared with placebo, pergolide reduced periodic limb movements of sleep and the numbers of hours a day with restless legs by a very considerable extent, while placebo was without effect (Figure 1). Five of eight patients had almost no restless leg symptoms with pergolide.

Figure 1: Pergolide effects on leg movements compared with placebo

Munich [3]


This was a longer-term trial with six weeks of treatment, and had more patients than the other trials. There were highly statistically significant improvements on almost every measure of sleep and leg movement. Using a scale from zero (no restless legs) to 10 (severe symptoms), patients on pergolide rated their symptoms below 1 on average, while on placebo the same patients rated their symptoms at 5 to 7 during the day and at night respectively (Figure 2). The absolute number of periodic leg movements during sleep and wakefulness was 46 on pergolide and 438 on placebo.

Figure 2: Patient rating of restless leg severity on pergolide and placebo

Adverse effects


There were no adverse effect withdrawals on pergolide and one on placebo. Adverse effects were usually nausea, headache and constipation, and usually mild. Nausea was treated with domperidone 60 mg.

Comment


These results, albeit in three relatively small but high-quality trials, look very good. Using the outcome of complete or almost complete relief of restless leg symptoms, the best information is that 16/19 patients benefited with pergolide compared with 1/19 controls. This would give a relative benefit of 11 (95% confidence interval 2.3 to 52) and a number needed to treat of 1.3 (1.0 to 1.7).

Whether this is sufficient evidence to institute this treatment in primary care is another matter. The results are such that local prescribing committees might like to examine it as part of formulating guidelines, and update that as more studies are reported. Because the studies we have were done on patients with bad symptoms (they were referred to neurologists, after all), a trial in primary care might be justified. An old-fashioned review has some interesting comments on diagnosis [4].

As always, Bandolier shows that evidence can be found, and where it can be found, even if, as here, it is for an unlicensed indication. Whether and how it should be used is up to the reader.

References:

  1. J Staedt et al. Pergolide: treatment of choice in restless legs syndrome and nocturnal myoclonus syndrome. A randomized crossover trial of pergolide versus L-dopa. Journal of Neural Transmission 1999 104: 461-8.
  2. CJ Early et al. Randomized, double-blind, placebo-controlled trial of pergolide in restless leg syndrome. Neurology 1998 51: 1599-1602.
  3. TC Wetter et al. A randomized controlled study of pergolide in patients with restless legs syndrome. Neurology 1999 52: 944-50.
  4. VG Evidente, CH Adler. How to help patients with restless leg syndrome. Postgraduate Medicine 1999 105: 59-74.
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