Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a common condition 
characterized by an irresistible urge to move the legs, concomitant with an 
unpleasant sensation in the lower limbs, which is typically relieved by 
movement. Symptoms occur predominantly at rest and prevail in the afternoon or 
evening. Treatment of patients with RLS/WED is indicated for those patients who 
suffer from clinically relevant symptoms. The management of mild forms of 
RLS/WED is mainly based on dopamine agonists (DA) therapy (including pramipexole 
and ropinirole) and α-2-δ calcium-channel ligand. Nevertheless, with passing of 
time, symptoms tend to become more severe and the patient can eventually develop 
pharmacoresistance. Furthermore, long-term treatment with dopaminergic agents 
may be complicated by the development of augmentation, which is defined by an 
increase in the severity and frequency of RLS/WED symptoms despite adequate 
treatment. Here, we discuss which are the best therapeutic options when RLS/WED 
becomes intractable, with a focus on advantages and side effects of the 
available medications. Prevention strategies include managing lifestyle changes 
and a good sleep hygiene. Different drug options are available. Switching to 
longer-acting dopaminergic agents may be a possibility if the patient is 
well-tolerating DA treatment. An association with α-2-δ calcium-channel ligand 
is another first-line approach. In refractory RLS/WED, opioids such as 
oxycodone-naloxone have demonstrated good efficacy. Other pharmacological 
approaches include IV iron, benzodiazepines such as clonazepam, and 
antiepileptic drugs, with different level of evidence of efficacy. Therefore, 
the final decision regarding the agent to use in treating severe RLS/WED 
symptoms should be tailored to the patient, taking into account the 
symptomatology, comorbidities, the availability of treatment and the history of 
the disease.