Can restless legs be ‘ironed out’?

Restless leg syndrome (RLS)^[1] is a neurological disorder characterized by uncomfortable sensations in the legs and momentary relief upon movement. The sensations, which are commonly reported^[2] as electrical, prickling, burning, tingling, and itching, typically worsen at night, when individuals are more likely to rest. This can be incredibly disruptive to sleep quality, which is why RLS is also classified as a sleep disorder^[3].

The condition is estimated to affect 10% of the U.S. population and, as you can see in Figure 1, is more prevalent in women^[4] than in men. It’s also more prevalent in individuals of western European descent^[5] than those of Asian descent. Researchers believe that there is a strong genetic^[6] basis to RLS, since individuals with a family history of RLS are also very likely to have the disorder. Genome-wide association studies^[7] have identified variants in six different genes linked to RLS. While much remains unknown, some of these genes have been linked to the development of neurons^[8].

Despite this, much evidence^[9][10] suggests that dysfunctions in the basal ganglia and in dopamine-producing neurons play roles in the pathology of RLS. These areas are responsible for controlling smooth muscle, which is involved in controlling involuntary movements like those in the digestive tract. Dysfunctions in the brain regions that control these muscles can lead to disruptive involuntary movements. More evidence to support the role of dopamine dysfunction in RLS comes from individuals with Parkinson’s disease, a degenerative condition in which dopamine-producing cells in the brain die at a rapid rate. These individuals are also more likely^[11] to develop RLS.

The American Academy of Sleep Medicine currently recommends^[12] dopamine agonists (drugs that activate specific dopamine receptors) as evidence-based treatments for RLS in its clinical practice guidelines. A 2011 Cochrane systematic review^[13] and meta-analysis of 38 randomized controlled trials also found that dopamine-agonists were effective in reducing symptoms of restlessness in individuals with RLS, when compared to placebo. However, participants taking dopamine agonists also had an 82% higher chance of experiencing adverse events, which may make such treatments undesirable for some.

Researchers have also looked to the role of iron^[14] in the pathology of RLS, since iron is a cofactor for an enzyme involved in the production of dopamine and because people with iron deficiencies have a higher frequency^[15] of RLS. Furthermore, there seems to be an association between the severity of iron deficiency^[16] and the severity of restlessness in RLS. It’s also hypothesized that central nervous system iron deficiency^[17] contributes to the dysfunction of dopamine in the brain.

Several randomized trials over the years have found improvements in RLS after iron supplementation. However, the American Academy of Sleep Medicine concluded that iron supplementation was not shown to be effective for RLS. These conclusions were based on a systematic review^[12] and meta-analysis conducted in 2012, but since then, several randomized trials have investigated the effects of iron on RLS. The current study aimed to update the conclusions of previous reviews by taking into account the data from more recent trials.

Restless leg syndrome is a neurological disorder that results in uncomfortable sensations in the legs that are temporarily relieved by movement. Symptoms typically get worse at night and can affect sleep quality. Dysfunctions in dopamine transmission and deficiencies in iron are believed to be involved in the pathology of the condition. Iron supplements have shown some promise in individual clinical trials, but large reviews in the past have concluded that there was no benefit. The current review is an update of previous reviews and takes into account more recent clinical trials.