New therapy recommendations for restless legs syndrome

Restless Legs Syndrome (RLS for short) is considered one of the most common neurological diseases in Western industrialized countries. Diagnosis and proper therapy often occur late and represent a major socioeconomic burden for the health care system, among other things due to the high augmentation rate, an amplification of symptoms due to too high a dose of therapy with dopamine-acting drugs. A new S2k guideline from the DGN and DGSM sheds new light on the understanding of the clinical picture and the recommended treatment options.
Restless legs illustration AndreyPopov / iStock

Restless Legs Syndrome

According to Prof. Dr. Claudia Trenkwalder, one of the authors of the new guideline on restless legs syndrome, the high level of suffering experienced by those affected reduces their quality of life enormously. She says it is important to make the latest research available to all treatment providers in order to provide all sufferers with the best possible diagnosis and therapy.

RLS patients suffer from an urge to move their legs at night, which is often associated with insensations and pain. This often results in sleep disturbances and reduced sleep quality. Consequences such as depression and daytime fatigue or chronic exhaustion are also noticeable.

Picture of aching leg AndreyPopov / iStock

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 diagnose restless legs syndrome, sufferers must meet all of the five diagnostic criteria. For further confirmation, the response to dopaminergic therapy is often also tested and an examination in the sleep laboratory is carried out. For differential diagnosis, blood count examinations are also always carried out to rule out renal insufficiency or iron deficiency diseases. The determination of iron levels should remain a fixed component of the examinations from the time of diagnosis. A systematic questioning about the current intake of medication should also be carried out in order to exclude a drug side effect as a cause. Before a therapy is initiated, comorbidities should be diagnosed and specifically treated, since the syndrome could also occur as a consequence of a pre-existing disease.

Therapy measures are usually based on the individual suffering of the affected person. If RLS occurs with comorbidities, therapy should initially be based on the diagnosed comorbid condition; if the cause of the condition is unknown, only symptomatic treatment is possible.

New guideline on restless legs syndrome

Together with the German Sleep Society (DGSM), the German Neurological Society (DGN) recently presented a new S2k guideline on restless legs syndrome. In contrast to the diagnostic criteria developed in 2014 and agreed upon in a consensus conference, the exclusion of differential diagnoses is now explicitly recommended for better differentiation from other clinical pictures.

Knee examination at the doctor sasirin pamai / iStock

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.

Blood sample with ferritin luchschen / iStock

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.


Restless legs syndrome is characterized by a high prevalence and by a high level of suffering among those affected. The new Sk2 guideline recommends a slow-onset, symptom-oriented treatment, taking into account the severity of the syndrome and the effects on sleep and quality of life. Greater importance is given to the control and optimization of iron metabolism, as well as to starting drug therapy as late as possible. Based on these recommendations, non-drug treatment options are moving further into the foreground and should be used more by those affected themselves. Exercise therapy and physiotherapy are of great importance in this context.

Olivia Malvani, BSc

Olivia Malvani, BSc

Last updated on 06.12.2022


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