Pramipexole (Mirapex) is a non-ergot selective dopamine receptor agonist that has been used since 1997 for the treatment of idiopathic Parkinson's disease. It is now labeled for the treatment of moderate to severe restless legs syndrome (RLS),¹ which is defined as having symptoms at least two to three days per week for at least three months and having a baseline score higher than 15 on the 40-point International Restless Legs Syndrome Study Group Rating Scale.²

SAFETY

Adverse effects occur less often with the lower doses of pramipexole used to treat RLS than with the higher doses used to treat Parkinson's disease. Approximately 6 percent of patients with Parkinson's disease who are treated with pramipexole have reported daytime drowsiness compared with 3 percent of those treated with placebo. Case reports have described episodes of falling asleep while engaged in normal activities, including driving. This sudden somnolence may occur up to one year after starting treatment and may not be preceded by warning signs.³ These events have only been reported by patients treated with pramipexole for Parkinson's disease, and not by patients treated for RLS. To minimize the risk of daytime somnolence, patients should be given the lowest effective dose.³

Hallucinations, pathologic gambling and other compulsive behaviors, and orthostatic hypotension are uncommon in patients taking higher doses of pramipexole for Parkinson's disease and are seen even less in patients taking lower doses for RLS. Pramipexole is U.S. Food and Drug Administration pregnancy category C.

Augmentation of RLS symptoms with long-term therapy occurs in approximately one fourth of patients taking pramipexole.^1,4 Symptoms may begin earlier in the evening, become more severe, and spread to the arms and trunk. Rebound or recurrence of RLS symptoms in the early morning also may occur over time; one study reported an incidence of 13 percent.⁴ Initiating therapy earlier in the day is often effective at controlling these symptoms; however, increasing the dose may worsen augmentation, requiring alternative therapies (e.g., opioids) to attain control.

TOLERABILITY

Nausea and sedation will occur in up to 30 percent of patients.^1,4–6 Approximately 7 percent of patients with RLS receiving pramipexole discontinued treatment because of adverse effects compared with 5 percent of patients receiving placebo.¹

EFFECTIVENESS

In the first three months of treatment, approximately 60 percent of patients receiving pramipexole instead of placebo will have at least a 50 percent reduction in symptoms; however, there is a profound placebo effect, and 42 percent of patients receiving placebo will also report this reduction. Approximately six patients need to be treated with pramipexole instead of placebo for one additional person to have a decrease in symptoms.^6,7 On average, all studied doses (0.25, 0.5, and 0.75 mg) produce the same reduction of RLS symptoms, so patients should be started on the lowest dose (0.125 mg) and only titrated to higher doses as needed.^4–6 Symptoms will recur when treatment is stopped. Pramipexole has not been directly compared with any other treatments for RLS.

PRICE

The approximate monthly cost of pramipexole 0.25 mg is $45; higher doses are more expensive.

SIMPLICITY

The starting dosage of pramipexole is 0.125 mg taken once daily two to three hours before bedtime. If needed, the dosage may be doubled every four to seven days up to a maximal dosage of 0.5 mg daily. The duration between titration steps should be increased to 14 days in patients with a creatinine clearance of 20 to 60 mL per minute (0.33 to 1.00 mL per second).¹ Pramipexole can be discontinued without tapering doses.

Bottom Line

Although many patients with RLS do not need pharmacologic therapy, pramipexole is one option for treating moderate to severe symptoms. As with other agents used to manage RLS, potentially serious adverse reactions are possible.