Medication treatment for restless legs syndrome (RLS) began with the opioids, which were first introduced as treatment in the 17th century and are still used today. Then came the benzodiazepines, the first “modern” treatment for RLS. Today, Sinemet and the dopamine agonists are first-line treatments—their efficacy make them the most commonly used medications.

The benzodiazepines are effective for mild cases of RLS, but are not typically used as a monotherapy and often necessitate combination with the opioids or a dopamine agonist. The opioids can be used in a number of clinical settings, and studies are being conducted to test their efficacy as a long-term monotherapy for certain patients.

The advent of dopamine agents, particularly Sinemet, has revolutionized RLS treatments. Studies show 90–100% initial efficacy. However, continued use of Sinemet can produce augmentation of a patient's symptoms. To combat augmentation a dopamine agonist like Permax is typically introduced, which has a much lower incidence of augmentation, but which must be built up slowly to enhance tolerability. Two new dopamine agonists, Mirapex and Requip, demonstrate therapeutic benefits but are not efficacious enough to replace the tested agonists.

While treatment of RLS has greatly improved over the history of the disorder, the search still continues for a single therapy that can effectively treat RLS patients over the long term without fear of augmentation and undesirable side effects.