RLS is treatable Non-pharmacological measures There are now a number of proven, effective therapies for RLS. However, the first issue for the clinician is whether or not pharmacological therapy is required. Non- pharmacological measures should be considered first in all but the most severe of cases. These included regular exercise, and improved sleep hygiene with regular sleep wake cycle and avoidance of alcohol, nicotine, and caffeine (Thorpy 2005). Patients may already have identified measures that they find helpful in preventing or ameliorating RLS symptoms. These may include physical activity such as stretching exercises just before bedtime; hot or, less often cold baths before bedtime; and mental activities that occupy them such as video games, conversation or even knitting. Nicotine, caffeine, alcohol, many antidepressants, antihistamines, most antinausea agents, and most antipsychotics have the potential to increase RLS symptoms or PLMS and should be avoided if possible. Pharmacotherapy: general principles Finding the best treatment for an individual patient usually proceeds in a ‘hit and miss’ fashion. Medications should be used at the lowest effective dose, and when necessary the dose should be titrated upward slowly. Medication should be given early enough to allow absorption and action before the onset of sleep; divided doses are often needed, most commonly with the evening meal and later at night. If the first agent does not work, then a second agent with a different mode of action should be substituted; sometimes a combination of medications works better than any single agent. Table 3 summarizes the double-blind randomized controlled trials reported to date. Many of the initial studies were small crossover trials, and it is only in recent years that relatively large scale studies have been conducted. Dopaminergic therapy Akpinar’s (1982) discovery that levodopa was dramatically effective in RLS revolutionized the management of RLS. Subsequently, every dopaminergic agent tested has been found to be effective against RLS and PLMS. Levodopa (with a dopa decarboxylase inhibitor) provides a remarkable near-immediate relief from RLS; this response is so characteristic that a brief trial of levodopa may be considered for patients in whom the diagnosis of RLS is in doubt (Benes et al, 1999). Levodopa is also extremely effective in Therapeutics and Clinical Risk Management 2006:2(4) Restless leg syndrome haemodialysis patients with RLS (Trenkwalder et al 1995). In general, levodopa is very well tolerated. Levodopa- induced dyskinesias have never been found in RLS patients. Studies with 18F-fluorodopa PET showing normal nigro- striatal binding capacities after more than 5 years of treatment in patients with RLS provide further confirmation of the safety of levodopa in this regard (Ruottinen et al 2000). Unfortunately, two troublesome and common problems develop with the prolonged use of levodopa and limit the value of this otherwise almost ideal agent for RLS: rebound and augmentation. Rebound is a consequence of the short half-life of levodopa; after a while, patients start to wake up at 4 AM or 5 AM with recurrence of their RLS. Addition of a sustained release preparation can delay the onset of rebound until later in the morning, although the long-term efficacy of this approach is not well established (Collado- Table 3 Medications shown to benefit idiopathic restless legs syndrome (RLS) in randomized double blind trials Medication Starting – usual dose Evidence base Dopamine precursors Levodopa +/- 50–200 mg at night benserazide Combined slow 100–200 mg at night and regular release levodopa Dopaminergic agonists Pergolide 0.025–0.5 mg daily Pramipexole Ropinirole Cabergoline 0.125–1.5 mg daily 0.25–3.0 mg daily 0.5–2.0 mg daily Rotigotine (patch) 1.125–4.5 mg daily Sedative-hypnotic agents Clonazepam 0.25–2 mg at night Antiepileptic agents Carbamezapine 100–300 mg daily Gabapentin 300–1500 mg daily Opioids Oxycodone 5–20 mg daily Abbreviations: RCT, randomized controlled trials; pts, patients. 3 RCTs, 58 pts 2 RCT 51 pts 3 RCTs 146 pts 2 RCTs 355 pts 4 RCTs 595 pts 1 RCT 85 pts 1 RCT 63 pts 1 RCTs 6 pts 1 RCT 174 pts 1 RCTs 24 pts 1 RCT 11 pts 471