More drugs hobble restless legs syndrome

June 4, 2007

Rotigotine, a investigational dopamine agonist, is being studied for treatment of restless legs syndrome.

Another investigational dopamine agonist, rotigotine-delivered via a transdermal patch-has been studied for both RLS and Parkinson's disease and, as Neupro (Schwarz Pharma), was just approved for Parkinson's. "The patch releases the drug continuously, with no drop in drug levels during early morning hours, so rotigotine should have less of a 'wearing-off effect' in the morning compared with other dopamine agonists," said Jack Chen, Pharm.D., associate professor in the movement disorders clinic at Loma Linda School of Medicine and Pharmacy in Southern California. This would prevent a recurrence of symptoms in the morning, a phenomenon sometimes seen with current dopaminergic therapies.

According to product labeling for dopamine agonists, hypotension may occur-even resulting in syncope. Dopamine agonists have also been associated with compulsive behaviors. But, as Chen noted, "they are not dose-related and they are clearly a class effect," as compulsions have occurred with both pramipexole and ropinirole.

Although the precise mechanism by which it acts in RLS management is unknown, gabapentin is used off label for treating RLS. In several small clinical studies in which gabapentin was studied in patients with RLS, the antiepileptic drug improved sleep quality and sleep latency and reduced leg movements during sleep. In fact, in several of the studies, gabapentin was just as effective as dopamine-acting drugs.

"Gabapentin might be used in RLS management when there is a simultaneous neuropathic pain component. Additionally, gabapentin might be added if patients are not getting adequate relief from a dopaminergic drug," said Chen.

Capitalizing on the benefits of gabapentin, Xenoport Inc. and GlaxoSmithKline have partnered to develop and commercialize a unique prodrug of gabapentin, known at this point only by the chemical name XP13512. This new drug reportedly has improved bioavailability compared with gabapentin.

Gabapentin is absorbed in the upper portion of the small intestine by a transporter that is easily saturated. This causes absorption of gabapentin to be dose dependent and to vary widely between patients. Rapid clearance of the drug also necessitates dosing three or more times per day to maintain therapeutic levels.

In contrast, XP13512 was designed to be absorbed throughout the length of the intestines, and when XP13512 is delivered via a sustained-release formulation, extended exposure to the drug enhances colonic absorption.

Although clearly the pharmacokinetic properties differ between gabapentin and XP13512, Chen cautioned that "it is too soon to tell whether XP13512 will offer clinical advantages over gabapentin" for RLS management.

THE AUTHOR is a clinical writer based in the Philadelphia area.