Periodic limb movements during sleep (PLMS) are a frequent finding in restless legs syndrome (RLS), but their impact on sleep is still debated, as well the indication for treatment.

We systematically reviewed the available literature to describe which drug categories are effective in suppressing PLMS, assessing their efficacy through a meta-analysis, when this was possible.

The review protocol was preregistered on PROSPERO (CRD42021175848) and the systematic search was conducted on PubMed and EMBASE (last searched on March 2020). We included original human studies, which assessed PLMS modification on drug treatment with a full night polysomnography (PSG), through surface electrodes on each tibialis anterior muscle. When at least 4 studies were available on the same drug or drug category, we performed a random effect model meta-analysis.

Dopamine agonists like pramipexole and ropinirole resulted the most effective, followed by L-Dopa and other dopamine agonists. Alpha2delta ligands are moderately effective as well opioids, despite available data on these drugs are much more limited than those on dopaminergic agents. Valproate and carbamazepine did not show a significant effect on PLMS. Clonazepam showed contradictory results. Perampanel and dypiridamole showed promising but still insufficient data. The same applies to iron supplementation.

Dopaminergic agents are the most powerful suppressors of PLMS. However, most therapeutic trials in RLS do not report objective polysomnographic findings, there’s a lack of uniformity in presenting results on PLMS. Longitudinal polysomnographic interventional studies, using well-defined and unanimous scoring criteria and endpoints on PLMS are needed.