By Timothy Tankosic, M.D.

The National Institute of Neurological Disorders and Stroke describes restless legs syndrome (RLS; also known as Ekbom's syndrome) as a common neurologic disorder characterized by unpleasant sensations (e.g., burning, creeping, tugging, or like insects crawling in the legs) in the legs and an urge to move when at rest in an effort to relieve these sensations. The paresthesias of RLS are generally worse during periods of inactivity or rest, while sitting or lying down, and during sleep. Movement of the legs can temporarily relieve the symptoms, but the combination of symptoms and movement to relieve them often results in difficulty falling and staying asleep and exhaustion and fatigue. RLS is a chronic and slowly progressive disorder. Prevalence estimates vary widely, from 12 million to more than 30 million adults in the U.S. The higher prevalence estimates are based on RLS is frequently misdiagnosed or remains undiagnosed.

It is estimated that only about 10% of those affected by RLS receive treatment. Dopaminergic agents (e.g., dopamine agonists and levodopa-carboxylase inhibitors) are considered to be the first line therapeutics for RLS. Augmentation of the symptoms of RLS, particularly onset occurring progressively earlier in the day, is a common problem encountered with the long-term use of dopaminergic drugs. The frequency appears to be less with dopamine agonists than with other types. Benzodiazepines (sedative-hypnotic agents), gabapentin and other antiepileptic drugs (AEDs), and opiates are also used to treat RLS. AEDs and opiates may be preferred when the condition is painful.

Dopamine agonism is the most common mechanism of action of drugs in development for RLS. Many of the drugs in development for RLS (or used off-label to treat it) are also in development or approved for Parkinson's disease. In May 2005, the dopamine agonist, Requip® (ropinirole; oral tablet; GlaxoSmithKline) became the first drug to receive FDA approval for RLS. The tables below list select drugs that are approved (one drug) or in development for RLS. New classes of drugs may soon be evaluated for RLS. The partial D2 (and D3) receptor agonist, aripiprazole (Abilify™; Bristol-Myers Squibb/Otsuka) is an atypical antipsychotic that acts principally at the dopamine receptor that has demonstrated activity against RLS (see Sleep. 2004 Aug 1;27(5):1022).

Suggested reading:

• Earley, CJ. Restless Legs Syndrome. NEJM. 2003;348:2103-9. (clinical review)
• Happe S, Trenkwalder C. Role of dopamine receptor agonists in the treatment of restless legs syndrome. CNS Drugs. 2004;18(1):27-36.
• Schapira AH. Restless legs syndrome: an update on treatment options. Drugs. 2004;64(2):149-58.

Selected drugs approved or in development for restless legs syndrome

Source D&MD

This review of emerging drugs for the treatment of restless legs syndrome was written by Timothy Tankosic, M.D. He may be contacted via e-mail at tt888@aol.com

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