Practice Guidelines: Restless Legs Syndrome

For the first time, the American Academy of Neurology has published practice guidelines for the management of restless legs syndrome (RLS).¹

“Roughly 2% of adults in the US have clinically significant RLS, suffering with clinically bothersome symptoms at least twice per week,” lead author John W. Winkelman, MD, PhD, an associate professor of psychiatry at Harvard Medical School and chief of the Sleep Disorders Clinical Research Program at Massachusetts General Hospital, told Neurology Advisor. In addition, over 80% of individuals who have RLS also suffer from periodic limb movement of sleep (PLMS), which is characterized by involuntary leg movements during sleep that cause significant sleep impairment.²

There are currently 4 FDA-approved RLS treatments, and a sizable body of research has investigated the efficacy of these and other approaches, including non-pharmacological strategies. In the new guidelines, the authors aimed to examine the available data to clarify which pharmacologic and nonpharmacologic treatments are safe and effective for RLS and related symptoms such as sleep and mood disturbances. The authors used the International Restless Legs Syndrome Study Group rating scale (IRLS) as the preferred outcome for RLS efficacy, of which they considered a change of 3 points to be clinically meaningful. They also considered objective and subjective outcomes pertaining to sleep, psychiatric symptoms, and quality of life.

Based on the strength of the evidence, the group produced 10 treatment recommendations summarized below.

1. Clinicians should consider a pharmacologic agent for patients with moderate to severe primary RLS. Strong evidence supports the use of pramipexole, rotigotine, cabergoline, and gabapentin enacarbil for this purpose. Evidence regarding the use of ropinirole, pregabalin, and IV FCM is moderate, and there is weak evidence regarding the use of levodopa. Few studies directly support the use of one agent over the other, though in practice, an agent is typically selected in the context of the patient’s comorbidities or potential adverse effects. 
2. For the treatment of sleep impairment in patients with primary RLS, the data supports several agents to varying degrees. For PLMS as measured by the Periodic Limb Movement Index (PLMI), strong evidence supports the use of ropinirole, while there is moderate support for the use of pramipexole, rotigotine, cabergoline, and pregabalin, and weak evidence regarding levodopa. When targeting sleep based on other objective measures such as total sleep time (TST), sleep efficiency, and sleep latency, there is moderate evidence supporting the use of ropinirole, gabapentin enacarbil, and pregabalin. In terms of subjective measures of sleep, the use of cabergoline and gabapentin are supported by strong evidence, while moderate evidence supports the use of ropinirole, pramipexole, and pregabalin. There is weak to moderate evidence pertaining to rotigotine, and weak evidence regarding levodopa.
3. For RLS with co-occurring psychiatric symptoms, there is moderate evidence for ropinirole in regards to anxiety and weak evidence for the drug in regards to depression. There is weak evidence for the use of pramipexole for depression and anxiety in RLS patients with moderate to severe mood impairment, and moderate evidence supports the use of gabapentin enacarbil for overall mood improvement.
4. Regarding agents that improve QoL, there is moderate evidence in support of ropinirole, pramipexole, cabergoline, gabapentin enacarbil, and IV FCM, and weak evidence supporting the use of rotigotine and pregabalin.
5. Regarding the risk of augmentation specifically, there is weak evidence suggesting that pregabalin should be considered over pramipexole in a 52-week course of treatment. Weak evidence also supports the use of cabergoline vs levodopa for a 30-week treatment course, though the risk of cardiac valvulopathy must be considered with cabergoline.
6. When patients have been unresponsive to other treatment approaches, the prescription of prolonged-release oxycodone/naloxone may be considered if available, though opioid-associated risks should also be considered. Weak evidence supports the use of this approach for the treatment of RLS symptoms, subjective sleep symptoms, and QoL.
7. Regarding the following agents, the evidence is insufficient to support recommendations for or against their use for RLS treatment: gabapentin, iron sucrose, oxycodone, clonazepam, bupropion, clonidine, selenium, rifaximin, botulinum neurotoxin, valproic acid, carbamazepine, and valerian.
8. When nonpharmacologic agents are preferred, there is moderate evidence to support the use of pneumatic compression, and weak evidence supporting the use of near-infrared spectroscopy (NIRS) and repetitive transcranial magnetic stimulation (rTMS). The use of vibrating pads for sleep problems–but not RLS symptoms–is supported by weak evidence.
9. Moderate evidence supports the use of ferrous sulfate with vitamin C for RLS treatment in patients with serum ferritin ≤ 75ug/L.
10. There is moderate evidence to support the prescription of vitamins C and E for patients with secondary RLS associated with end-stage renal disease who are on hemodialysis. This is the only cause of secondary RLS for which sufficient treatment evidence is available. Additionally, there is weak evidence to support the use of ropinirole, levodopa, and exercise in such patients.

Overall, the analysis shows that “there are medications from 3 different mechanistic classes which provide benefit in RLS – dopamine agonists, an alpha-2-delta calcium channel ligand, and iron. This indicates the complexity of the underlying pathophysiology of RLS but similarly the variety of potential approaches to its treatment,” noted Dr Winkelman.

Mia T. Minen, MD, MPH, of NYU Langone Medical Center in New York City, said, “The guidelines are helpful because they describe the evidence for treating both primary and secondary RLS,” noting that she also finds the recommendations pertaining to psychiatric comorbidities particularly useful. “As the incidence of RLS increases with age, and older people are more likely to have multiple comorbidities requiring increasingly complex treatments, these guidelines should be helpful in providing evidence behind the supplements, exercise, compression devices, and more which may be used in the treatment of RLS,” she told Neurology Advisor.

In terms of future investigations, Dr Winkelman says there is a need for more high-quality studies assessing long-term RLS treatment with any approach, as well as head-to-head trials comparing agents from different classes. “There is also a paucity of information on the most important complication of RLS treatment, augmentation, which is a worsening of RLS symptoms after treatment with dopaminergic medications,” he said. Research in this area should aim to elucidate the true incidence of augmentation, whether it is influenced by the drug’s duration of action, and whether it is possible to predict which patients will develop augmentation.

References

1. Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline: Treatment of restless legs syndrome in adults. Neurology. 2016; 87:1–9
2. Restless Legs Syndrome Fact Sheet. National Institutes of Health: National Institute of Neurological Disorders and Stroke. Published September 2010. Updated July 27, 2015. http://www.ninds.nih.gov/disorders/restless_legs/detail_restless_legs.htm