New therapy recommendations for restless legs syndrome

Typical symptoms are tingling, electric, pulling, stinging, burning, formication, pressure sensation, cramps, hot or cold sensation in the limbs, which appear mainly in the phases of physical rest or lying down. By yielding to the urge to move, the insensations are usually quickly relieved.

To date, the exact pathophysiological causes have not been clarified; current knowledge suggests a multifactorial development due to changes in iron and dopamine metabolism and a genetic predisposition. Low iron levels are detectable in many RLS sufferers and reinforce the assumption that the pathogenesis of the syndrome is associated with a disorder of iron metabolism. The association of the syndrome with an imbalance of the neurotransmitter dopamine has been known for a longer time. In several imaging studies, presynaptically increased and postsynaptically decreased dopamine concentrations could be shown. Furthermore, genetic factors play an important role in the development of the disease, which is shown by the often positive family history of the patients.

To clarify the causes, a precise history of the medications currently being taken should be taken in order to be able to include or exclude these as possible exacerbating factors of the syndrome. Another new feature is the replacement of the previous division into primary and secondary RLS by a single concept. According to this concept, the clinical picture of restless legs syndrome arises from interacting genetic, socioeconomic, and environmental factors as well as comorbidities. All these comorbid factors should be subject to early diagnosis and treatment, and the term "secondary RLS" should no longer be used.

For the choice of therapeutic measures, a slow and symptom-oriented approach is recommended. The S2k guideline initially recommends twice-daily oral iron substitution in combination with vitamin C for better absorption. In case of oral iron intolerance or moderate to high severity of RLS, iron should be administered intravenously once or twice a week. Alternatively, non-ergot dopamine agonists, including rotigotine, ropinirole, and pramipexole, have been shown to be effective and are approved in the D-A-CH region. Treatment with levodopa should be intermittent or for diagnostic purposes only.

As second-line medications, opioids (e.g., oxycodone/naloxone) can be used separately or in combination with a dopamine agonist or a gabapentinoid. Due to a lack of evidence, the guideline does not recommend therapeutic use of cannabinoids, magnesium, or benzodiazepines. To avoid augmentation, an increase in symptoms when the medication dosage is too high, the use of only one dopaminergic substance, dosed as low as possible, is recommended. In addition to medication or separately, non-drug therapy measures such as transcranial direct current stimulation, exercise training (bed bike, yoga, etc.), and infrared light therapy are advised. Current data are insufficient to recommend the use of acupuncture, pneumatic compression, endovascular laser ablation, cryotherapy, and phytotherapy. Worsening or amelioration of RLS symptoms by coffee, alcohol, nicotine, or other stimulants has still not been clarified in larger studies, according to the guideline. Treatment of symptoms in RLS with comorbid conditions, such as cardiovascular or psychiatric conditions, should be subject to careful review.

Augmentation should be diagnosed clinically by history and may be present if definitional criteria are met. The new guideline provides steps for augmentation treatment, including controlling iron metabolism as a first step.

In pregnant women, frequently occurring iron deficiency should be excluded or treated. In the first trimester, iron substitution should preferably be administered orally; from the second trimester, it can also be administered intravenously. Levodopa should not be combined with benserazide because of embryotoxic side effects, nor should dopamine agonists. Low-dose oxycodone or naloxone may be used, avoiding combination with acetaminophen, aspirin, or ibuprofen, for the treatment of very severe RLS in pregnancy. Because of insufficient data and possible risks to the unborn child, zolpidem/zopiclone and other benzodiazepine receptor agonists, as well as gabapentin and pregabalin, are not recommended for drug therapy. In children and adolescents, no drug therapy is recommended except for iron supplementation. Similarly, no statements were made for non-drug therapy measures for restless legs syndrome . The guideline points out the importance of good sleep hygiene.