Pramipexole: A nonergot-derived dopamine agonist for the treatment of restless legs syndrome

Formulary, March 1st, 2007

Abstract

Drugs that act to increase dopamine activity are the mainstay of pharmacologic treatment for restless legs syndrome (RLS), a sensomotor disorder that usually manifests as an urge to move the legs, with or without other uncomfortable sensations. Pramipexole, a nonergot-derived dopamine agonist previously approved by FDA for the treatment of Parkinson disease, received FDA approval for the treatment of moderate-to-severe RLS in November 2006. In placebo-controlled clinical trials, treatment with pramipexole improved RLS symptom scores and measures of sleep quality. Common adverse events included nausea, fatigue, headache, and somnolence. Sudden onset of sleepiness has also been reported rarely in patients being treated with pramipexole for RLS. Augmentation, a change in or worsening of symptoms after initiation of treatment, may occur in up to one-third of patients treated with this agent. More data are needed to better characterize the relative efficacy of pramipexole compared with other treatments for RLS and to clarify the rates of less common adverse events. (Formulary. 2007;42:165–174.)

Restless legs syndrome (RLS) is a sensomotor disorder that usually manifests as an urge to move the legs, with or without other uncomfortable sensations. Patients may experience symptoms daily or only intermittently; these symptoms generally occur during rest or other periods of inactivity. RLS is associated with involuntary muscle contractions, known as periodic limb movements, that most often occur during sleep (PLMS) but may also be present while the patient is awake (PLMW).1–3 All 4 of the key features of RLS should be present for clinical diagnosis: 1) there is an urge to move the legs, often accompanied by feelings of uncomfortable sensation; 2) the urges to move or sensations occur or worsen during times of rest or inactivity; 3) symptoms are ameliorated by movement; and 4) symptoms generally occur or are worse in the evening or night than in the daytime.1 Other factors that support the diagnosis are a family history of a first-degree relative with RLS and the presence of PLMS.1

In population surveys, approximately 10% of people report the presence of RLS symptoms on ≥5 nights each month, although some estimates place the prevalence of RLS in primary care practices closer to 15%.2,3 RLS appears to be more common in patients of Northern or Western European descent than in patients of Asian descent.3

RLS may be primary (idiopathic) or may develop secondary to other conditions such as chronic renal failure, iron deficiency, or pregnancy. Of these conditions, iron deficiency is most commonly associated with RLS, but it is unclear if RLS is only associated with iron deficiency or if low iron stores somehow lead to dysfunction in the dopamine system.3 One algorithm for the management of RLS published in 2004 recommended assessment of serum ferritin concentration, with ferrous sulfate replacement therapy recommended for patients with low-to-normal levels.2 Hypothyroidism, diabetes mellitus, rheumatoid arthritis, and Sjögren's syndrome have also been associated with RLS symptoms, although these associations are not well established.2–4 Symptoms of secondary RLS often remit if the contributing condition is resolved, as in the case of renal transplant or the end of a pregnancy.1,5

Current thinking has focused attention on the role of the dopaminergic system in the development of RLS symptoms. Some, though not all, studies have found modest reductions in brain dopamine function in patients with RLS.2,3 Also, use of medications that affect brain dopamine levels, including antidepressants, neuroleptic agents, and antiemetics, may contribute to RLS symptoms.2,3 It has been proposed that dopamine-related changes in behavior and mood are mediated by the D3 dopamine receptor, whereas motor effects are the result of D2 receptor activity.6 Increased dopaminergic activity as a result of treatment with levodopa or dopamine agonists has been demonstrated to suppress RLS symptoms, and symptom response to dopaminergic therapy supports the clinical diagnosis of RLS.1–3 As a result of this association between RLS symptoms and dopaminergic therapy, the nonergot-derived dopamine agonist pramipexole (Mirapex, Boehringer Ingelheim), which was previously approved by FDA for the treatment of Parkinson disease, received FDA approval in November 2006 for the additional indication of treatment for moderate-to-severe RLS, joining ropinirole (also a nonergot-derived dopamine agonist, approved for RLS in 2005) as a new treatment option for RLS.7–9

Despite the approval of these therapies specifically for RLS, the natural history of RLS is not well known, as most patients with mild or intermittent symptoms do not seek treatment. Symptoms may also vary greatly from patient to patient. In younger patients (aged <50 years), symptoms are typically insidious in onset, whereas symptom onset is usually acute in older patients. Regardless of the time to symptom onset, RLS is usually a chronic problem and may significantly affect the patient's sleep by causing difficulties in falling asleep (increasing sleep latency), reducing sleep time, or waking the patient from sleep.1

There is no standard measure to monitor RLS. Published clinical trials have assessed symptoms using several criteria. The Clinical Global Impression (CGI) and Patient Global Impression (PGI) scales rate symptom severity by assigning 1 of 7 ratings to symptoms, from "very much improved" to "very much worse." The 10-item International RLS Study Group (IRLS) scale is a validated instrument that patients use to self-classify RLS symptoms. Disease severity is classified as mild (score range, 1–10), moderate (range, 11–20), severe (range, 21–30), or very severe (range, 31–40). Published trials have also used several measures of quality of life (QOL), including the Restless Legs Syndrome Quality of Life (RLS-QOL) questionnaire (range, 0 [worst]–100 [best]) and general QOL measures such as the Short Form-36 (SF-36). Researchers often evaluate the effect of RLS on patients' sleep by analyzing sleep diaries or using standardized scales. Polysomnography (performed in a sleep laboratory) is also used to assess various sleep parameters and to record PLMS and PLMS index (the number of PLMS per hour).3,5

Once RLS has been diagnosed, healthcare professionals should recommend nonpharmacologic strategies and should assess possible secondary causes of RLS before initiating drug treatment for RLS. When possible, aggravating medications should be discontinued or doses should be reduced. Patients should be encouraged to practice good sleep habits; to avoid caffeine, nicotine, and alcohol; and to try engaging in activities such as puzzles or videos that increase mental alertness during times of boredom.2,4

Not every patient requires drug therapy, and treatment should be tailored based on patient complaints, symptom severity, and comorbid conditions. For bothersome RLS symptoms that persist despite trials of nonpharmacologic strategies, agents that increase dopamine activity, including carbidopa/levodopa and the dopamine receptor agonists ropinirole and pramipexole, have been demonstrated to reduce symptoms. A 2004 Academy of Sleep Medicine report described practice parameters (including off-label use of medications) for the use of dopaminergic agents to treat RLS.10 These guidelines used standard methods to grade available evidence for RLS treatments and to present the recommended treatments as either standard (treatment supported by a high degree of clinical certainty), guideline (a patient care strategy supported by a moderate degree of clinical certainty), or optional (treatment with uncertain clinical use). The practice parameters classified levodopa/carbidopa, pergolide, pramipexole, and ropinirole as effective for the treatment of RLS. At the time of publication of the guidelines, recommendations for levodopa/ carbidopa and pergolide were offered at the standard level, treatment with pramipexole at the guideline level, and treatment with ropinirole at the optional level. The algorithm for the management of RLS published in 2004 (which also included off-label use of medications) recommended the use of levodopa/carbidopa for the treatment of intermittent RLS symptoms and the use of dopamine receptor agonists such as pramipexole and ropinirole for the treatment of daily RLS.2

When dopaminergic agents are not tolerated, are ineffective, or are otherwise contraindicated, opioids, benzodiazepines or benzodiazepine agonists, or anticonvulsants (including gabapentin and carbamazepine) may be effective.2,4,10 In some cases, combination therapy with a dopaminergic agent and a benzodiazepine, opioid, or anticonvulsant may be used for adequate symptom control. Combination therapy is generally reserved for cases in which RLS symptoms do not respond to adequate doses of dopaminergic therapy, or in the case of intolerable adverse events or uncontrollable augmentation (a change in or worsening of symptoms after initiation of treatment).2,11 The timing of medications should be matched to the onset of symptoms (usually early evening or bedtime), with adjustments as needed. Treatment may reduce the symptoms of RLS, but these agents are not curative.

Since publication of the 2004 practice parameters, both ropinirole and pramipexole have gained on-label FDA approval for the treatment of RLS.

CHEMISTRY AND PHARMACOLOGY

Pramipexole is a nonergot-derived agonist at dopamine D2 receptors with strong affinity for the D3 receptor subtype; this agent has greater affinity for the D3 receptor subtype than ropinirole, but it is unclear how that relates to the clinical use of these agents.6 Pramipexole has very little activity at D1 receptors or at serotonin (5-HT2A or 5-HT2B) receptors.6,7 A more specific mechanism for the action of pramipexole in RLS has not been well characterized.

PHARMACOKINETICS

Pramipexole has an absolute bioavailability >90% and achieves peak concentrations in 2 hours. Administration of pramipexole with food delays the time of maximum concentration but does not affect the extent of absorption. Pramipexole does not appear to undergo significant first-pass metabolism.7 It has a high volume of distribution and is approximately 15% protein bound. Pramipexole is largely excreted as unchanged drug and is secreted by the renal tubules with clearance of approximately 400 mL/min. Renal impairment may have a significant effect on the pharmacokinetics of pramipexole. The half-life of pramipexole is approximately 8 hours in healthy volunteers and 12 hours in elderly patients.7

CLINICAL TRIALS

Open-label studies. The first clinical series describing the use of pramipexole for RLS symptoms was published in June 1998.12 The results of this series and subsequent open-label studies in patients with primary RLS are summarized in Table 1.12–17 These open-label evaluations generally included patients with similar demographic profiles; the studies enrolled both male and female patients aged approximately 60 years. Although some patients were treatment naïve, the majority had experienced treatment failure with other agents for RLS, including levodopa. In all studies, pramipexole was initiated at 0.125 mg administered 2 hours before the usual onset of symptoms, and the dose was titrated upward based on efficacy and adverse events. The majority of patients experienced improvement in RLS symptoms with pramipexole, including reduction of leg restlessness and involuntary movements, improvements in sleep quality measures, and improvements in rating scale scores, including the IRLS scale. Two studies followed up with patients on long-term pramipexole therapy and documented continued benefit.15,17

Most recently, Montplaisir et al18 published the results of a telephone survey that evaluated the long-term efficacy and adverse events of pramipexole therapy in patients with no previous exposure to dopaminergic agents. Clinic records were reviewed to identify eligible patients who had a diagnosis of primary RLS and were undergoing pramipexole treatment that had been initiated >12 months earlier. A total of 196 patients were eligible for the study, and 195 patients agreed to participate. At the time of the telephone survey, 152 patients were still taking pramipexole; the remainder had discontinued treatment because of adverse events (n=20), lack of efficacy (n=6), both (n=6), or other reasons (n=11). Patients who had discontinued were more likely to have been diagnosed with milder disease before treatment than patients who were still taking pramipexole. The mean duration of pramipexole therapy for patients who were still taking the drug at the time of the survey was 30.5±10.5 months. Of those who had continued treatment, the mean pramipexole dose was 0.59±0.31 mg (range, 0.125–2.25 mg), and the mean RLS symptom severity score had decreased from baseline by 80%±20.8%. Ninety-four percent of patients reported a decrease in symptom severity of ≥50%. Patients also reported improvements in RLS symptoms that had caused them to wake at night or to have difficulties in falling asleep. The authors concluded that pramipexole was effective for the long-term treatment of RLS in drug-naïve patients.

Pramipexole was also evaluated in an open-label study in patients with RLS secondary to renal insufficiency.19 Ten patients on hemodialysis who had RLS symptoms severe enough to interfere with dialysis sessions were treated with pramipexole (dose range, 0.125–0.5 mg) and were followed for a mean of 8 months. Primary efficacy measures included changes in the IRLS score and PLMS index. Mean IRLS scores fell from a baseline of 25.8±5.75 to 7.7±8.36 (P<.005) after treatment, and the mean PLMS index was reduced from 108.7±42.38 at baseline to 38.4±27.46 after treatment (P<.001). No significant differences were found on other measures of sleep quality. The authors suggested that pramipexole was effective for the treatment of secondary RLS in patients undergoing hemodialysis, but this indication requires additional study.

Randomized, placebo-controlled trials. Six randomized, placebo-controlled trials of pramipexole for RLS have been published.20–25 All of these studies evaluated patients with primary RLS and enrolled patients with IRLS scores >15, indicating a symptom severity of moderate, severe, or very severe. Most of the studies excluded patients with a variety of medical conditions that could affect RLS or RLS treatments. Studies that reported clinical outcomes, as opposed to results from polysomnography only, are summarized in Table 2.22–24

The first randomized, controlled trial to evaluate pramipexole for the treatment of RLS was published by Montplaisir et al in 1999.20 This 10-week, double-blind, placebo-controlled, crossover study enrolled 10 men and women aged 20 to 65 years with RLS as defined by the RLS Study Group. Patients were excluded if they had any condition associated with RLS, had a PLMS index <10, had any other sleep disorders, or were using any other medications that might affect sleep patterns in the 2 weeks before the study. The study design included two 4-week treatment periods with a 2-week washout between periods. Patients spent four 2-night evaluation periods in a sleep laboratory at baseline and at the end of Weeks 4 (first treatment period), 6 (washout), and 10 (second treatment period). The primary outcomes of the study were the PLMS and PLMW indices from the sleep laboratory recordings. Secondary outcomes included sleep latency and efficiency. Patients received pramipexole or placebo tablets 1 hour before bedtime. The initial dose of pramipexole was 0.375 mg, with increases after 1 and 2 weeks to a final dose of 1.5 mg.

Of the 9 patients who completed the study, 6 were able to tolerate the 1.5-mg daily dose. As reported on home questionnaires, pramipexole significantly reduced leg restlessness during each time period studied, including during the evening and overnight. Pramipexole produced a 98% decrease in both the number and index of PLMS as compared with placebo. There were no significant differences between pramipexole and placebo on measures of sleep latency or efficiency.

The authors studied 7 of the patients who completed this study in a separate trial to determine if the therapeutic effect of pramipexole continued after 6 months of continuous treatment and if patients treated with pramipexole developed rebound morning restlessness or augmentation.26 Pramipexole therapy was initiated at 0.25 mg 1 hour before bedtime, and the dose was increased weekly until symptom relief was obtained. The mean effective dose was 0.5 mg. Patients completed questionnaires to record the presence of symptoms at various times throughout the day. The authors observed a significant reduction (P=.028) in leg restlessness at bedtime and nighttime after 1 month of treatment with pramipexole. There was no evidence of a decrease in effect after long-term use (mean, 7.8 months) and no evidence of morning rebound or augmentation.

Saletu et al21 performed a single-blind, placebo-controlled, unbalanced, crossover sleep laboratory study to determine the acute effects of pramipexole when used to treat RLS. Eligible patients were those who had a diagnosis of RLS with stable symptoms for the 2 weeks before the study. Patients were excluded if they had another sleep disorder, neuropathy, or various psychiatric diagnoses that might affect RLS symptoms. Patients were evaluated on 3 nights: a pretreatment night, a placebo night, and a drug night. Patients received 0.088 mg pramipexole base (equivalent to 1.25 mg dihydrochloride) at 9:00 PM and 0.18 mg pramipexole at 10:30 PM on the drug night. Various sleep quality measures were recorded overnight, including PLMS, total sleep time, sleep efficiency, sleep stages, and sleep latency to each stage. The primary outcome was the measure of PLMS per hour of total sleep time. Patients also completed subjective assessments of sleep and RLS symptoms and mental performance tests upon awakening. Patients then entered a 4-week, open-label, follow-up phase in which the dose of pramipexole was titrated to optimal effect or until further increases were limited by persistent adverse events. Efficacy was assessed with the IRLS scale.

Eleven patients (8 men and 3 women) were enrolled in the study, and all but 1 completed the 4-week follow-up period. In the acute phase, the primary outcome of PLMS index was improved from 35.0±55.5 at baseline to 8.2±6.1. Pramipexole also improved total sleep time by a median of 18% (P=.017) and improved sleep efficiency by a median of 19% (P=.002) compared with placebo. The investigators concluded that, overall, pramipexole treatment resulted in significant differences (P<.05) in objective measures of sleep quality compared with placebo. Patients' subjective reporting of sleep quality was also improved with pramipexole treatment. There were no differences between pramipexole and placebo on mental performance the morning after treatment. After 4 weeks of follow-up treatment, IRLS scale scores improved from a pretreatment score of 23±7 to 13±10 (P=.004).

Partinen et al22 performed a double-blind, placebo-controlled, parallel-group, fixed-dose study that evaluated various doses of pramipexole for the short-term treatment of RLS. Eligible patients were those with moderate-to-severe idiopathic RLS according to the IRLS rating scale, a PLMS index ≥5 on baseline polysomnography, and weekly RLS symptoms that had affected sleep in the previous 3 months. Patients were excluded if they had other medical or psychiatric problems that might affect sleep or RLS measures. Eligible patients also could not be taking other treatments for RLS. Patients were randomized to 1 of 4 pramipexole groups (0.125, 0.25, 0.5, or 0.75 mg) or placebo; treatment lasted for 3 weeks. The primary outcome was change from baseline in the PLMS index at the end of the study. The investigators also evaluated RLS symptoms, CGI and PGI ratings, sleep quality, daytime somnolence, and QOL.

A total of 109 patients were randomized to 1 of the 5 groups, and 107 of these patients were included in the intent-to-treat analyses. The mean age of patients in the intent-to-treat population was 56.2 years, and 41.1% of these patients had received treatment for RLS previously. After 3 weeks, the PLMS index was significantly reduced with all doses of pramipexole. Mean change from baseline was –26.55 to –52.7 for pramipexole-treated patients and –3 for placebo-treated patients. Pramipexole treatment also significantly improved IRLS scores. Mean change from baseline ranged from –11.87 to –17.01 for pramipexole-treated patients versus –6.08 for placebo-treated patients. More patients in the pramipexole groups responded that symptoms were "much better" or "very much better" than in the placebo-treated group, although this difference only achieved statistical significance for the 0.5- and 0.75-mg groups. Likewise, more patients treated with pramipexole versus patients in the placebo group were rated as "much improved" or "very much improved" by clinicians using the CGI severity scale. This difference was statistically significant for all but the 0.125-mg group. Subjective sleep quality improved in all groups, including small changes in the groups treated with pramipexole 0.125 mg or placebo, and no group demonstrated evidence of daytime sleepiness. Overall QOL measures were not significantly different among groups, although some pramipexole-treated groups demonstrated a positive change on the SF-36 Social Functioning subscale.

A 2006 study by Oertel et al23 described the results of a larger-scale, double-blind, randomized, placebo-controlled trial of pramipexole for the treatment of moderate RLS. A total of 345 patients aged 18 to 80 years were randomized to receive either pramipexole or placebo 2 to 3 hours before bedtime for 6 weeks. Doses of pramipexole were initially 0.125 mg but were titrated upward weekly for the first 4 weeks of the study based on efficacy and adverse events. Prior treatments for RLS, if used, were discontinued 14 days before the study. Patients were excluded if they had significant endocrine, hepatic, renal, gastrointestinal, or pulmonary disorders or other neurologic disease.

The primary end points were change from baseline in IRLS scores and percentage of patients with CGI-Improvement (CGI-I) scale ratings of "much improved" or "very much improved" at the end of the study. The investigators also evaluated the percentage of patients with ≥50% reduction in IRLS scores ("IRLS responders") and PGI scores. Patients who reported their symptoms as "much better" or "very much better" were termed "PGI responders." Adverse events were also monitored to determine the safety of pramipexole. Patients were specifically asked about "sleep attacks," or sudden onset of sleepiness, but not about signs of augmentation.

A total of 338 patients completed postbaseline assessments and were included in the intent-to-treat population. (~69%) had not received treatment for RLS previously. The mean age of patients was 55 years, and approximately two-thirds of the patients were women. At baseline, the mean IRLS scores demonstrated that patients had moderate-to-severe RLS (pramipexole group, 24.7±5.2; placebo group, 24.9±5.4). At Week 6, both primary end points favored pramipexole treatment. Change in IRLS score from baseline was –12.3±0.6 for the pramipexole group versus –5.7±0.9 for the placebo group (P<.0001). Among pramipexole-treated patients, 62.9% had CGI-I ratings of "much improved" or "very much improved" compared with 32.5% of placebo-treated patients (P<.0001). Secondary end points also favored pramipexole treatment, including the proportion of IRLS responders (pramipexole, 52.2%; placebo, 28.9%; P<.0001) and the proportion of PGI responders (pramipexole, 61.6%; placebo, 31.6%; P<.0001). Differences between the pramipexole and placebo groups were evident after 1 week of treatment. Pramipexole treatment also significantly improved sleep satisfaction and tiredness or sleepiness as assessed by selected items on the IRLS questionnaire.

A study by Winkelman et al24 enrolled patients similar to those in the Oertel et al23 study, although patients with diabetes or other endocrine, hepatic, renal, gastrointestinal, or pulmonary disorders were allowed to enroll. A total of 345 patients were randomized to treatment with 1 of 3 fixed doses of pramipexole (0.25, 0.5, or 0.75 mg/d) or placebo in this 12-week, double-blind, placebo-controlled, parallel-group, fixed-dose study. Pramipexole was initiated at 0.125 mg and increased weekly to the target dose over 3 weeks. The primary measures of efficacy included change from baseline on the IRLS scale and the proportion of CGI-I responders. Secondary end points included the number of IRLS responders, PGI scale ratings, RLS-QOL results, measures of daytime somnolence, and visual analog scale (VAS) scores for symptom severity assessed before sleep onset.

A total of 339 patients were included in the efficacy analyses. The mean age of patients was 51.4 years. Approximately 62% of patients were women, and approximately 22% had received treatment for RLS previously. The mean IRLS score for all patients at baseline was 23.45, indicating moderate-to-severe RLS. Both primary end points significantly favored treatment with pramipexole, but there was also a substantial placebo response (Table 2). Secondary measures of PGI responders and VAS scores of symptom severity also significantly favored pramipexole, although not for all dose groups. Measures of daytime sleepiness were similar among pramipexole- and placebo-treated patients. Treatment with pramipexole significantly improved RLS-QOL scores for all dose groups.

A study by Trenkwalder et al25 evaluated the sustained long-term efficacy of pramipexole compared with placebo in patients who had responded well to pramipexole in a 6-month open-label trial. Eligible patients for the open-label trial included men and women aged 18 to 80 years from multiple sites in Germany. All patients had primary RLS and baseline IRLS scores >15. Those with medical conditions that might affect RLS treatment were excluded. The open-label trial followed patients on 1 of 4 doses of pramipexole (0.125–0.75 mg); doses were optimized individually for each patient. Upon completion of the open-label trial, patients who had a CGI-I rating of "much improved" or "very much improved" and an IRLS rating <15 were then randomized to receive continued pramipexole or placebo for another 3 months to evaluate the effects of therapy withdrawal.

The primary outcome measure for the randomized, controlled withdrawal period was time to "insufficient response," a composite of a CGI-I score of "minimally worse," "much worse," or "very much worse" and an increase in IRLS score >15. Other outcome measures included CGI-I rating, PGI rating, RLS-QOL results, and measures of sleep quality and daytime sleepiness.

Ninety-one percent of patients randomized to receive pramipexole were able to complete the 3-month controlled withdrawal period compared with 35% of placebo-treated patients. Those who were randomized to continued pramipexole treatment had a significantly greater time to an insufficient response event than those who were randomized to placebo. Insufficient response occurred in 20.5% of pramipexole-treated patients versus 85.5% of placebo-treated patients (P<.0001). Within 1 week of randomization, placebo-treated patients had a mean increase in IRLS score of 14.9 versus a 2-point mean increase for patients treated with pramipexole (P<.0001). Most other measures, including CGI-I, CGI severity, and CGI efficacy ratings; PGI ratings; and RLS-QOL results, also favored continued pramipexole treatment. Measures of daytime sleepiness were not significantly different between groups. The authors concluded that the effects of pramipexole were sustained over 9 months of treatment. This study also demonstrated the rapid symptom return that occurs when pramipexole treatment is discontinued.

Published reports of pramipexole for the treatment of RLS have not used an active control arm, and head-to-head trials with other dopaminergic agents are not available. Studies also have not specifically addressed the use of pramipexole in combination therapy for RLS, although 1 study allowed patients taking other medications for sleep (including benzodiazepines and levodopa) to continue taking these medications concurrently with pramipexole treatment.14

ADVERSE EVENTS

In published studies, treatment with pramipexole was generally well tolerated. Adverse events that occurred more often with pramipexole than with placebo in randomized trials included headache, nausea, fatigue, and somnolence, similar to the adverse events observed with ropinirole.8,22–24 Nausea was usually transient, resolving within 14 days.2 Nasal stuffiness, constipation, insomnia, fluid retention, and leg edema were also reported, although these were less common and usually resolved when treatment was discontinued.2 Valvular heart disease has been reported with ergot-derived dopamine agonists (including pergolide and cabergoline), but this complication has not been reported with pramipexole in published clinical trials. Most randomized trials assessed changes in vital signs including heart rate and blood pressure, but no significant effects were observed. Orthostatic hypotension was reported rarely and was determined to be of mild severity.22,23

A significant disadvantage to the use of carbidopa/levodopa is a phenomenon known as augmentation, a change in or worsening of symptoms after initiation of treatment that cannot be explained by any other psychiatric, behavioral, or pharmacologic factors.1 Augmentation may manifest as worsening RLS symptoms earlier in the day after an evening dose of medication, earlier onset of symptoms by ≥2 hours, increased intensity of symptoms, or spread of symptoms to the arms.1,2 Up to 83% of levodopa users experience augmentation at some point during treatment, and the risk appears to increase with higher doses or continuous use.1 Augmentation has also been reported with other RLS treatments, including pergolide, ropinirole, and pramipexole, although the data on augmentation are limited by small sample sizes, lack of a standard definition of augmentation until 2003, and differing patient populations in published studies.1,27 It is generally thought that the risk of augmentation is worse with levodopa than with dopamine receptor agonists.1 Augmentation may be managed by discontinuing the agent or by moving the dosing time to earlier in the day. 2,15,17 The occurrence of augmentation with 1 agent does not predict response to a similar agent, so it is reasonable to try another agent within the same class.2,4

Several studies have specifically assessed augmentation risk with the long-term use of pramipexole.14,15,17 Rates of augmentation in these studies ranged from 8.3% to 33%. There was not a predictable time to onset of augmentation, with reports of onset ranging from 1 to 3 months of treatment to 31 months of treatment. In most cases, augmentation did not lead to discontinuation and was treated by moving doses to earlier in the day or by adding additional doses of pramipexole. One study specifically evaluated the development of tolerance to pramipexole, necessitating larger doses of the medication to maintain the original effect.17 Tolerance occurred in 46% of patients and was correlated with previous augmentation with levodopa and a history of tolerance to levodopa.

Levodopa therapy for RLS has also been associated with a rebound phenomenon wherein patients experience a worsening of symptoms at the end of the dosing period, often in the late night or early morning. This is most often associated with regular-release forms of carbidopa/levodopa because of the short half-life of the agent.2,14 Rebound has not been reported with pramipexole.17

Somnolence and sleep attacks during activities of daily living have been reported in patients taking pramipexole for the treatment of Parkinson disease.7 Somnolence was reported in 3% to 10% of pramipexole-treated patients with RLS in randomized trials.22–24 Sudden sleep onset was not reported in all studies of pramipexole for RLS, but 1 study documented sleep attacks in 3 patients taking pramipexole 0.25 to 0.5 mg and in 2 patients taking placebo.24 In the same study, somnolence was reported more often in pramipexole-treated patients than in placebo-treated patients, but measures of daytime sleepiness demonstrated no significant difference between groups. It has been proposed that somnolence and sleep attacks are less common when pramipexole is used to treat RLS, possibly because of the lower doses used.2

DRUG INTERACTIONS

Unlike ropinirole, pramipexole does not undergo significant hepatic biotransformation and therefore is not expected to interact with other CYP enzyme substrates, inducers, or inhibitors at doses used clinically.6–8 Administration of pramipexole with drugs that are renally secreted by cationic transport (such as cimetidine, ranitidine, diltiazem, and verapamil) can result in a modest decrease in clearance, but dose adjustments are not required.6,7

DOSAGE AND ADMINISTRATION

Most studies of pramipexole for the treatment of RLS used an initial dose of 0.125 mg taken orally 2 to 3 hours before bedtime (or symptom onset). Doses were increased in 0.125-mg or 0.25-mg increments every 4 to 7 days until patients reported adequate symptom relief or until adverse events limited further dose increases. There is limited evidence that doses higher than 0.5 mg provide additional benefit in RLS.7 Mean therapeutic doses in most studies that allowed dose titration were approximately 0.35 mg daily. There is no need for adjustments to dose or titration schedule based on age, sex, or weight, but renal insufficiency can reduce clearance of pramipexole by 75% compared with clearance in healthy volunteers. The manufacturer recommends conservative initial dosing and a 14-day titration period in patients with renal dysfunction (creatinine clearance, 20–60 mL/min).7 A negligible amount of pramipexole is removed by dialysis; however, 1 small open-label study described the successful use of pramipexole to treat secondary RLS symptoms in patients on hemodialysis.19 Patients with renal insufficiency were excluded from most studies of pramipexole for RLS, and the manufacturer advises exercising caution when using pramipexole in patients with renal disease.7

PRICING

Average wholesale prices for pramipexole range from $135 per 90-day supply of 0.25-mg tablets to $217 per 90-day supply of 1.5-mg tablets. Ropinirole tablets are similarly priced at $203 for 100 tablets of the 0.25-, 0.5-, 1-, and 2-mg strengths or $247 for 100 tablets of the 3-, 4-, and 5-mg strengths.28

References

1. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisir J. Restless legs syndrome: Diagnostic criteria, special considerations, and epidemiology: A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4:101–119.

2. Silber MH, Ehrenberg BL, Allen RP, et al. An algorithm for the management of restless legs syndrome. Mayo Clin Proc. 2004;79:916–922.

3. Hening WA, Allen RP, Earley CJ, Picchietti DL, Silber MH. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep. 2004;27:560–583.

4. Happe S, Trenkwalder C. Role of dopamine receptor agonists in the treatment of restless legs syndrome. CNS Drugs. 2004;18:27–36.

5. Ryan M, Slevin JT. Restless legs syndrome. Am J Health-Syst Pharm. 2006;63:1599–1612.

6. Kvernmo T, Härtter S, Bürger E. A review of the receptor-binding and pharmacokinetic properties of dopamine agonists. Clin Ther. 2006;28: 1065–1078.

7. Mirapex [package insert]. Ridgefield, Conn: Boehringer Ingelheim International GmbH; 2006.

8. Requip [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2006.

9. Mirapex label and approval history. Drugs@FDA website. Available at: http://www.fda.gov/cder/foi/appletter/2006/020667s011,%20020667s013ltr.pdf|~ . Accessed February 12, 2007.

10. Littner MR, Kushida C, Anderson WM, et al; Standards of Practice Committee for the American Academy of Sleep Medicine. Practice parameters for the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep. 2004;27:557–559.

11. Kushida C. Pramipexole for the treatment of restless legs syndrome. Expert Opin Pharmacother. 2006;7:441–451.

12. Lin S-C, Kaplan J, Burger CD, Fredrickson PA. Effect of pramipexole in treatment of resistant restless leg syndrome. Mayo Clin Proc. 1998;73: 497–500.

13. Becker PM, Ondo W, Sharon D. Encouraging initial response of restless legs syndrome to pramipexole. Neurology. 1998;51:1221–1223.

14. Ferini-Strambi L. Restless legs syndrome augmentation and pramipexole treatment. Sleep Med. 2002;3:S23–S25.

15. Silber MH, Girish M, Izurieta R. Pramipexole in the management of restless legs syndrome: An extended study. Sleep. 2003;26:819–821.

16. Stiasny-Kolster K, Oertel WH. Low-dose pramipexole in the management of restless legs syndrome: An open label trial. Neuropsychobiology. 2004;50:65–70.

17. Winkelman JW, Johnston L. Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome (RLS). Sleep Med. 2004; 5:9–14.

18. Montplaisir J, Fantini ML, Desautels A, Michaud M, Petit D, Filipini D. Long-term treatment with pramipexole in restless legs syndrome. Eur J Neurol. 2006;13:1306–1311.

19. Miranda M, Kagi M, Fabres L, et al. Pramipexole for the treatment of uremic restless legs in patients undergoing hemodialysis. Neurology. 2004;62:831–832.

20. Montplaisir J, Nicolas A, Denesle R, Gomez-Mancilla B. Restless legs syndrome improved by pramipexole. Neurology. 1999;52:938–943.

21. Saletu M, Anderer P, Saletu-Zyhlarz G, Hauer C, Saletu B. Acute placebo-controlled sleep laboratory studies and clinical follow-up with pramipexole in restless legs syndrome. Eur Arch Psychiatry Clin Neurosci. 2002;252:185–194.

22. Partinen M, Hirvonen K, Jama L, et al. Efficacy and safety of pramipexole in idiopathic restless legs syndrome: A polysomnographic dose-finding study—The PRELUDE study. Sleep Med. 2006;7:407–417.

23. Oertel WH, Stiasny-Kolster K, Bergtholdt B, et al; for the Pramipexole RLS Study Group. Efficacy of pramipexole in restless legs syndrome: A six-week, multicenter, randomized, double-blind study (effect-RLS study). Mov Disord. 2007; 22:213–219.

24. Winkelman JW, Sethi KD, Kushida CA, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology. 2006;67:1034–1039.

25. Trenkwalder C, Stiasny-Kolster K, Kupsch A, Oertel WH, Koester J, Reess J; the German RLS-Pramipexole Study Group. Controlled withdrawal of pramipexole after 6 months of open-label treatment in patients with restless legs syndrome. Mov Disord. 2006:21:1404–1410.

26. Montplaisir J, Denesle R, Petit D. Pramipexole in the treatment of restless legs syndrome: A follow-up study. Eur J Neurol. 2000;7(suppl 1):27–31.

27. Trenkwalder C. The weight of evidence for ropinirole in restless legs syndrome. Eur J Neurol. 2006;13(suppl 3):21–30.

28. Red Book. 2006 edition. Montvale, NJ: Thompson PDR; 2006.