What are the first-line pharmacological treatments for adults diagnosed with Restless Legs Syndrome (RLS)?

First-line pharmacological treatments for adults diagnosed with Restless Legs Syndrome (RLS) are alpha-2-delta ligands, specifically pregabalin or gabapentin, both used off-label. These are preferred especially for people with severe sleep disturbance, comorbid insomnia or anxiety, RLS-related or comorbid pain, or a history of impulse control disorder (ICD) ¹.

Dopamine agonists, previously first-line, are now generally reserved for specific cases such as short-term use during restricted movement (e.g., plane travel) or when gabapentinoids are not tolerated or ineffective. Their use requires careful monitoring due to risks of augmentation (worsening symptoms requiring dose increase) and impulse control disorders ¹.

Iron supplementation should be considered if serum ferritin is below 50–75 micrograms/L, as iron deficiency can exacerbate RLS symptoms. Iron therapy probably improves RLS severity and restlessness ¹.

Opioids (e.g., codeine or tramadol) may be considered as alternatives, particularly for painful RLS symptoms, but with caution due to dependence risk. Drug dosages should be kept to the minimum effective dose to reduce adverse effects ¹.