Dopaminergic agents are considered to be the first-line treatment for RLS, including pramipexole and ropinirole (Garcia-Borreguero et al., 2013; Silber et al., 2013). Pergolide and cabergoline are not recommended due to their association with increased risk of valvular heart disease (Zanettini et al., 2007). Ropinirole has a faster onset with shorter duration, while rotigotine is commonly used as a transdermal patch which continuously provides stable plasma drug concentrations, resulting in its particular therapeutic effect on patients with symptoms throughout the day (Mackie and Winkelman, 2015). α2δ agonists have become increasingly important in treating RLS, for being considered as possible first-line agents for RLS. A recent double-blind study over 12-week period compared the efficacy of pregabalin, pramipexole and placebo, demonstrating a better efficacy of pregabalin rather than dopamine agonist or placebo (Hubner et al., 2013). Moreover, the difference of the efficacy varied with drug doses (Hubner et al., 2013). Opioids have been found to be effective in treating RLS, but the potential drug abuse and side effects including respiratory depression and constipation limit its use in RLS, as they are not commonly advised as initial treatment of choice. A recent study on treating first-line agents refractory RLS with extended-release oxycodone–naloxone combination showed very impressive and persistent effect of this combination on RLS symptoms (Trenkwalder et al., 2013). Other pharmacological treatments include iron supplement, some other anticonvulsants and benzodiazepines. The choice of two major first-line agents should be considered with their side effects. Dopamine agonists can cause somnolence and ICDs like compulsive gambling or over-eating, while common side effects of α2δ agonists are weight gain, dizziness and gait instability. As a result, for initial treatment of RLS patients, dopaminergic agents are used as first-line agents in patients with very severe symptoms, over-weighted, comorbid depression, risk of falls, or cognitive impairment (Garcia-Borreguero et al., 2013), while α2δ agonists are advised as first-line agents in patients with severe sleep disturbance, comorbid anxiety, RLS-related pain, or previous history of ICDs (Garcia-Borreguero et al., 2013). Evidence-based guidelines on treating RLS were published by EFNS and IRLSSG in 2012 and 2013 respectively. Many other pharmacological treatment reviews and research papers of RLS have been published recently (Garcia-Borreguero and Williams, 2014; Hornyak et al., 2014). A conclusion of several medications is shown above (Table 4).