Restless legs: the first-line drugs just changed places

The drugs that doctors reach for first in restless legs syndrome have been reversed. The 2024 American Academy of Sleep Medicine guideline now recommends against the routine use of the dopamine agonists that were long the standard treatment, because taken over months and years they frequently make the condition worse — a paradox called augmentation — and instead gives its strongest backing to three anticonvulsants and to correcting low iron [s1].

That is close to an inversion of the previous US guidance, which had rated the same dopamine agonists as having the strongest supporting evidence [s3]. The change is not a new discovery so much as a reweighting: long-term harms that were once a footnote are now the deciding factor. This is an account of what the guideline says, not medical advice, and iron dosing and drug choice are decisions for a clinician.

What restless legs syndrome is

Restless legs syndrome is a common neurological condition in which an irresistible urge to move the legs, often with uncomfortable sensations, builds during rest and in the evening and eases with movement — a pattern that wrecks sleep [s1]. Periodic limb movement disorder, covered by the same guideline, involves repetitive limb movements during sleep [s1]. The guideline's first step is not a drug at all: it advises checking for and addressing things that make symptoms worse, including alcohol, caffeine, some antihistamines and antidepressants, and untreated sleep apnoea [s1].

The augmentation problem

Augmentation is the reason for the reversal. With long-term dopamine-agonist use, symptoms can start earlier in the day, spread to other parts of the body, and become more intense than before treatment — the drug that helped at first ends up amplifying the disease [s1]. For each of the dopamine agonists, the 2024 guideline attaches the same remark: the drug may still suit patients who value short-term symptom relief and place less weight on long-term adverse effects, "particularly augmentation" [s1].

What changed, in the guideline's own gradings

The old US guidance, an American Academy of Neurology practice guideline from 2016 that has since been retired, gave its top rating (Level A, strong evidence) to pramipexole, rotigotine, cabergoline and gabapentin enacarbil, with ropinirole and pregabalin one tier down [s3]. Dopamine agonists sat at the front of the line.

The 2024 AASM guideline moves them to the back. It issues strong recommendations, at moderate certainty of evidence, for the alpha-2-delta anticonvulsants — gabapentin enacarbil, gabapentin and pregabalin — and for intravenous ferric carboxymaltose in patients with appropriate iron status [s1]. It then suggests against the standard use of pramipexole (moderate certainty), ropinirole (moderate certainty) and transdermal rotigotine (low certainty), all as conditional recommendations, and issues a strong recommendation against cabergoline [s1]. The evidence behind these calls came from a companion systematic review that screened 3,631 studies and analysed data from 148 [s2].

Iron, and the thresholds that guide it

The guideline treats iron as central rather than adjunctive. It advises testing serum ferritin and transferrin saturation in everyone with clinically significant restless legs, and — as a consensus good-practice statement rather than a strongly evidenced one — suggests supplementing iron when serum ferritin is at or below 75 ng/mL or transferrin saturation is under 20%, and using intravenous iron only when ferritin sits between 75 and 100 ng/mL [s1]. These thresholds are higher than those used for iron deficiency in the general population, which is part of why the condition is under-treated [s1].

The limits

Most of the recommendations against dopamine agonists are conditional, not strong, and several rest on low or very low certainty evidence [s1]. The guideline does not ban these drugs; it reframes them as a short-term option for selected patients rather than a default [s1]. And much of the underlying trial evidence is of limited quality, which the systematic review states plainly [s2].

Why it matters

Restless legs is a case where the drug that works best this week is not the one that serves a patient best over years, and the guidance has finally been rewritten around that gap [s1][s3]. For restless legs in pregnancy and its link to perinatal mood, see perinatal sleep, insomnia and restless legs; for how the evidence rates sleeping pills against non-drug options, see CBT-I versus hypnotics; and for another guideline built on cautious dosing, see melatonin for insomnia.

Sources

• Treatment of restless legs syndrome and periodic limb movement disorder: an AASM clinical practice guideline — Journal of Clinical Sleep Medicine, 2024-09-26
• Treatment of restless legs syndrome and periodic limb movement disorder: an AASM systematic review, meta-analysis, and GRADE assessment — Journal of Clinical Sleep Medicine, 2024-09-26
• Practice guideline summary: Treatment of restless legs syndrome in adults (retired) — Neurology, 2016-11-16