Restless legs syndrome: Diagnostic time-savers, Tx tips

Typical doses of carbidopa/levodopa as a treatment for RLS are 25/100 mg to 100/400 mg in divided doses, given before bedtime and again, if needed, in the middle of the sleep period.⁹ These doses are much lower than those used to treat Parkinsonism.

Common side effects of carbidopa/levodopa include nausea, headache, dry mouth, and daytime somnolence.^2,21 An increased risk of melanoma has been seen in some studies of carbidopa/levodopa, but the evidence is inconclusive.^23,24 Rebound (a worsening of symptom severity when the medication wears off) and augmentation (the development of more severe symptoms early in the day) have also been reported.

Tolerance to carbidopa/levodopa is infrequent among patients with RLS. One early study found that only 3 of 43 patients (7%) required an increase in dosage over time.²¹ The on/off phenomenon that occurs with this medication in the treatment of Parkinsonism is not mentioned in the literature in reference to RLS.

Because carbidopa/levodopa only provides relief for 4 to 6 hours, a second dose is often needed. If that second dose repeatedly disrupts the patient’s sleep, the recommended approach is to give 2 doses before bedtime—1 dose of regular carbidopa/levodopa and 1 dose of the controlled release form.^6,9

Augmentation, the most serious problem associated with carbidopa/levodopa, occurs in 65% to 80% of RLS patients treated with this medication. It is more common in those with refractory symptoms and those taking higher doses, but can affect any RLS patient.

If augmentation develops, discontinue the carbidopa/levodopa and switch the patient to another agent. Augmentation reverses within a few weeks of stopping the medication and treatment can then be resumed, but be aware that the augmentation may reoccur.

Carbidopa/levodopa is a good choice for patients with intermittent RLS symptoms, despite the risks associated with this medication. Not only does it provide quick relief, but it can be used only on the days when symptoms occur.^2,5,8

Dopamine agonists

The use of pramipexole or ropinirole as first-line treatment for people with daily or refractory symptoms of RLS is well supported by controlled studies.^7,17,25 Dopamine agonists can also be used to treat patients with RLS with varying levels of severity,⁶ and are sometimes prescribed as the initial treatment for intermittent symptoms.

These newer agents have a longer half-life than carbidopa/levodopa, which eliminates the need for a second dose in the midst of the sleep cycle. They also have much lower rates of augmentation. Studies have been inconsistent with regard to the risk of augmentation associated with these drugs, however, with results ranging from a high of 33%^7,26 to a low of 4%.²⁷

Nausea, headache, fatigue, dizziness, orthostatic hypotension, and vomiting—the most common side effects of pramipexole and ropinirole—usually decrease in severity after 7 to 10 days of therapy. In a recent meta-analysis comparing dopamine agonists with placebo in RLS patients, the number needed to harm (NNH) was 77 and the number needed to treat (NNT) was 6.²⁷

Pramipexole. Dosing is started at 0.125 mg at bedtime and slowly titrated up to minimize side effects. Most patients experience relief at an average dose of 0.375 mg, taken daily or intermittently for symptom relief. ^6,17,27

Ropinirole. Dosing is started at 0.25 mg at bedtime (or at dinner and bedtime), and then slowly titrated up every few days to every week until a good response is obtained. Most patients respond to a dose between 1 and 2.5 mg/d.^6,17,28

Tx alternatives: Anticonvulsants, opioids, and benzodiazepines

When patients are unable to tolerate—or do not respond adequately to—dopaminergic agents or dopamine agonists, anticonvulsants, opioids, or benzodiazepines may be effective alternatives, or adjunctive treatments. They may also be used in patients who have another disorder, such as chronic pain, for which these alternatives will be beneficial.

Anticonvulsants. Of the anticonvulsants studied in RLS patients, gabapentin has been shown to most effectively decrease symptoms.²⁵ Use of the drug should be reserved for patients with daily symptoms or refractory RLS. Gabapentin also appears to be especially effective in patients who perceive their symptoms as painful, and in hemodialysis patients.^2,17,28 The average effective daily dose of gabapentin for treatment of RLS is 1855 mg.⁶

A 2002 double-blind crossover trial found that after 6 weeks of therapy, 16 of 24 (66%) patients taking gabapentin had only mild RLS symptoms, compared with 8 of 24 (33%) of those taking placebo (NNT=3).¹⁴ The most common side effects were malaise, somnolence, dry mouth, and nausea (NNH=4). Of note, there was no significant difference in the incidence of side effects among those in the therapy group compared with the controls.