Cotter and O’Keefe Seidel et al 1999). Augmentation is a more serious problem. This phenomenon has a number of components: symptoms develop at an earlier time in the day; they may become more severe; there may be a reduced time at rest to onset of symptoms; finally, symptoms may develop in parts of the body that were not previously involved such as the arms. Up to 80% of patients treated with levodopa have some augmentation symptoms after a few months, and about a third have sufficiently severe symptoms that a change in therapy is required (Allen and Earley 1996). For this reason, levodopa is no longer the treatment of choice for RLS, although it remains valuable for those with only intermittently severe symptoms. Dopamine agonists are now regarded as the first-line treatment for RLS. The non-ergot agonists pramipexole, ropinirole and rotigotine, as well as the ergot derived cabergoline and pergolide, have all been shown to benefit RLS in randomized controlled trials (Table 3). Open label studies suggest that dopamine agonists are well tolerated in patients with severe RLS who have failed other therapies and also in those with augmentation (Stiasny, Wetter, et al 2000). However, while initial reports using pramipexole suggested that augmentation was very uncommon with this agent, a recent study of prolonged treatment has suggested levels of augmentation and tolerance of 32% and 46% respectively (Winkleman and Johnston 2004). These levels are still much lower than seen with levodopa, though they seem more likely to occur in those patients who previously developed similar problems with levodopa. Dose modification may be required if augmentation or tolerance develop, but, unlike the situation with levodopa, a change in medication is rarely needed. The largest clinical trials to date have been conducted using ropinirole. In two 12-week multinational studies, ropinirole significantly improved RLS symptoms, associated sleep disturbance and quality of life of RLS patients and was generally well tolerated (Trenwalder et al 2004; Walters et al 2004). Augmentation was not seen during the study periods. However, the differences in symptom improvement between placebo and ropinirole did not attain the pre- determined clinically significant difference. Two factors may be of relevance: a large placebo response has present in both studies and the international RLS rating scale used as a primary outcome may have been insufficiently responsive to change. Other medications Antiepileptic agents Carbamazepine 100–400 mg at night has been shown in randomized trials to be effective in relieving paresthesias and in reducing the number of attacks of RLS (Telstad et al 1984). However, side effects were very common, and, increasingly, gabapentin, which is also effective but seems better tolerated, is preferred (Garcia-Borreguero et al 2002). Antiepileptic agents may have a particular role in patients with painful paraesthesias or an underlying neuropathy. In general, RLS can be treated with much smaller dosages than are required to control seizures. Opioids Opioids were described as useful in the treatment of RLS by Willis. Oxycodone has been proven in a small controlled study to give symptomatic improvement and to reduce PLMS (Walters et al 1993). There is, of course, the risk of dependence with this class of medication, and they should be avoided in those with a history of addiction. Nevertheless, opioids retain a role in the treatment of particularly refractory cases of RLS (Walters et al 2001). . Benzodiazepines Clonazepam was effective in a double-blind crossover study of 6 RLS patients (Montagna et al 1984). It is likely that the main effect of benzodiazepines in this population is mediated by sleep promotion (Saletu et al 2001). Given the very limited evidence of benefit and the risks of sedation and falls, these agents should usually be avoided in RLS. Treatment of secondary RLS The management of the secondary causes of RLS involves correction of the underlying problem where possible. Treatment of iron deficiency, with or without anemia, by oral iron supplements has been reported to improve or resolve RLS symptoms. The benefit seems most clear cut in those with almost certain iron deficiency, as indicated by a serum ferritin less than 20 mcg/L. However, even those with probable iron deficiency, and a serum ferritin between 20 mcg/L and 50 mcg/L may also benefit from iron supplements; hence, the current recommendation to maintain a serum ferritin greater than 50 mcg/L in RLS patients. There seems little benefit from oral iron in those with ferritin levels more than 50 mcg/L (Davis et al 2000). Standard treatment is ferrous sulphate 325 mg daily, with or without vitamin C, 472 Therapeutics and Clinical Risk Management 2006:2(4)