Treatment

Consideration of management of restless legs syndrome (RLS) in an adult:

The American Academy of Sleep Medicine (AASM) recommend that the first step in the management of RLS should be addressing exacerbating factors, such as alcohol, caffeine, antihistaminergic, serotonergic, antidopaminergic medications, and untreated obstructive sleep apnoea (1).

Non-pharmaceutical based measures include:

• avoidance of alcohol, caffeine, and smoking
• good sleep hygiene
• moderate regular exercise
• avoidance of overexertion, stress, or sleep deprivation
• brief walking or other motor activities, hot baths, or leg massage before bedtime

Iron levels in RLS

In all patients with clinically significant RLS, clinicians should regularly test serum iron studies including ferritin and transferrin saturation (calculated from iron and total iron binding capacity)

• testing should ideally be administered in the morning avoiding all iron-containing supplements and foods at least 24 hours prior to blood draw (1)
• iron deficiency plays a central upstream role in neurotransmitter synthesis, transport, and synaptic regulation
  • as a cofactor for tyrosine hydroxylase, iron is essential for dopamine synthesis, and its deficiency reduces dopamine production and dopamine transporter (DAT) activity, thereby disrupting synaptic dopamine homeostasis
  • dysfunction of the dopamine system is a significant hypothesis for the pathophysiology of RLS (2)
• if iron deficiency anaemia, or serum ferritin less than 90 μg/L
  • initiate investigation to identify a possible cause of iron deficiency
  • patients with a serum ferritin of less than 90 μg/L should be started on iron supplements (3)
  • noted that anaemia is not sufficiently sensitive as a marker for iron deficiency (3)

α2δ calcium channel ligands (pregabalin or gabapentin)

• in recent years, the therapeutic potential of α2δ calcium channel ligands such as gabapentin and pregabalin has gained prominence in the treatment of RLS
• recommended as first-line recommended drug options for people with frequent or daily symptoms
• the use of pregabalin or gabapentin in RLS is off-licence for both medications
• note that this class of medications can have adverse effects, including dizziness and somnolence, which may influence shared decision-making for prescribers and patients (1)
• medication dosages should be kept to the lowest required for symptomatic improvement; as the risk of adverse effects with these is medications is proportional to dose
• pregabalin (3)
  • initial dose: 75 mg in people aged under 65 years and 50 mg in people aged over 65 years
  • there is not any specific guidance on dose titration and the requirement for divided daily doses
    • note that for another indication (neuropathic pain), divided doses are advised, and it is recommended that initial pregabalin dose can be doubled after 3–7 days, and then increased incrementally on a weekly basis to the maximum dose if required
• gabapentin (3)
  • initial dose: 300 mg if the person is under 65 years old and 100 mg if the person is over 65 years old
  • there is not any specific guidance on dose titration and the requirement for divided daily doses
  • note that or other indications it is recommended that gabapentin therapy is initiated at 300 mg once daily on day one, twice daily on day two, and three times daily on day three, followed by further increases in 300 mg/day increments every 2–3 days to the maximum dose if required

Weak opioids (such as codeine or tramadol), taken intermittently or regularly (depending on symptoms), is an alternative

• weak opioids (codeine or tramadol) can be used intermittently or daily for painful RLS
• the clinician must however consider the risk of opioid dependence when prescribing opioids

Dopamine agonists

• non-ergotamine dopamine agonists e.g. pramipexole, ropiniprole
• ergotamine dopamine agonists (e.g. cabergoline, pergolide) less preferred due to side effects

• dopamine agonists are no longer used as first-line treatment for RLS, because the of complications associated:
  • augmentation (suggested by a worsening of RLS accompanied by the need to increase the dose of dopamine agonist) (2)
    • augmentation refers to a drug-induced paradoxical worsening of RLS symptoms, often presenting as an earlier onset of symptoms in the day, increased symptom severity, or spread to other body parts
    • risk of augmentation increases with higher doses (>0.5 mg/day for pramipexole or >4 mg/day for ropinirole), prolonged use, and evening or multiple daily dosing
    • 10-year cumulative incidence of augmentation with dopamine agonists has been reported to exceed 60% in some cohorts
  • risk of developing impulse control disorder

Note that dopamine agonists may still be indicated for individual patients based on circumstances and patient preference

• AASM guidance notes that either ropinirole or pramipexole may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation)
• in patients currently using these medications then clinicians should avoid abrupt discontinuation of dopamine agonists, as this may precipitate dramatic rebound RLS – consult local guidance and expertise regarding a long term dose reduction plan in these circumstances

Reference:

1. Winkelman JW et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2025 Jan 1;21(1):137-152.
2. Xu Y, Guan Y, Lang B. Unraveling Restless Legs Syndrome: A Comprehensive Review of Current Research and Future Directions. Int J Gen Med. 2025 Jul 23;18:4041-4055.
3. NHS Nottinghamshire Area Prescribing Committee (March 2023). Restless legs treatment algorithm (Accessed October 8th 2025).