Dopaminergic Agents
Levodopa
The medication most studied for RLS is oral levodopa combined with a dopa decarboxylase inhibitor (carbidopa or benserazide). The dopa decarboxylase component prevents the peripheral conversion of levodopa to dopamine. Thus, more levodopa is available to cross the blood-brain barrier. The benserazide-levodopa combination is not available in the United States but is more common than carbidopa-levodopa in the rest of the world.
There have been three double-blind, placebo-controlled trials of levodopa and a dopa decarboxylase inhibitor that enrolled 20 or more RLS patients.[69,70,71,72] Twenty-eight idiopathic or uremic RLS patients were evaluated in a crossover trial of benserazide-levodopa or placebo for four-week treatment periods.[69] The response of subjects to treatment was assessed by polysomnography, actigraphy, a sleep diary, and quality-of-life assessments. Fifteen patients took one capsule containing benserazide 25 mg and levodopa 100 mg, while 13 patients escalated to two capsules after inadequate response at two weeks of treatment. Patients given benserazide-levodopa had decreased PLMS for the first four hours after dosing compared with placebo (p = 0.005). Five and six hours after dosing, the number of PLMS increased nonsignificantly compared with placebo (p = 0.232). Patients also increased their total sleep time (p = 0.045) and rated their quality of sleep as better (p = 0.002) compared with placebo patients. Quality of life was improved with benserazide-levodopa in both life satisfaction (p = 0.010) and negative feelings and complaints (p = 0.024).
In the study by Benes et al.,[70] 35 patients with RLS were given either benserazide-levodopa or placebo in a crossover design with each treatment period lasting four weeks. PLMS were monitored using actigraphy. Subjects also completed the Standardized Sleep Inventory Schlaf-Fragebogen, part A (SF-A), and a quality-of-life questionnaire. Doses could be adjusted according to RLS response to a maximum of benserazide 50 mg and levodopa 200 mg; 84% of participants received the maximum dose. The number of PLMS per hour were reduced with benserazide-levodopa treatment (p < 0.0001), mainly within the first five hours of sleep. On the Standardized Sleep Inventory SF-A, subjects rated sleep quality as improved and more refreshing during the benserazide-levodopa period (p = 0.0002); quality of life also improved with benserazide-levodopa (p = 0.003). Improvement was noted as early as the first night of therapy, demonstrating the usefulness of benserazide-levodopa in intermittently occurring RLS.
In an unusually designed study that supports the immediate effectiveness of benserazide-levodopa, 20 patients with RLS were given benserazide-levodopa alternating with placebo every other day.[71] Patients rated their preference for either treatment at the end of the study. Seventeen patients preferred benserazide-levodopa (p < 0.01); three patients had no relief from either treatment.[71] Smaller, placebo-controlled, open-label studies support the use of levodopa with either benserazide or carbidopa for RLS.[73,74,75,76,77,78,79]
To determine if patients who continued treatment with benserazide-levodopa sustained RLS improvement, von Scheele and Kempi[80] reviewed the records of 30 RLS patients who had been maintained on benserazide-levodopa for at least two years. Two patients reported loss of effect after one month of treatment. Nine patients had an increased dose on review compared to their initial dose. Twenty-two patients continued to report improved sleep duration (p < 0.001), and 17 reported a reduced number of awakenings (p < 0.001) compared to baseline.
Common adverse effects of levodopa seen in these trials were nausea, headaches, and dry mouth.[69,70] Dyskinesias do not develop with levodopa use in RLS as they do in Parkinson's disease.[81] Two therapeutic problems that are unique to RLS are rebound and augmentation. Rebound is the return of symptoms as medication wears off and is directly related to the half-life of the medication.[81] This phenomenon occurs in 20-35% of patients taking levodopa.[51] The half-life of carbidopa-levodopa is 0.75-1.5 hours; thus, some patients have good symptom control in the first half of the sleeping period, but then symptoms return after 5 to 6 hours.[81] Two studies have been conducted to address this concern.[72,82] The combination of regular-release and sustained-release benserazide-levodopa was examined in a study of 30 RLS patients who were documented responders to regular-release benserazide-levodopa and who demonstrated worsening RLS symptoms in the second half of the night.[72] Subjects were stabilized on the regular-release product for two weeks and then added either sustained-release benserazide-levodopa or placebo in a crossover fashion for four weeks in each treatment period. Response to treatment was measured by actigraphy and quality-of-life questionnaires completed by the patients. Subjects on combination therapy had decreased numbers of PLMS (p < 0.0001), and they rated their sleep quality as improved (p < 0.001). No difference was seen in quality of life between the two study groups. In the second study, 20 patients with RLS were given either the regular-release or sustained-release formulation of carbidopa 25 mg with levodopa 100 mg at bedtime, both of which provided symptom relief.[82] During the mean follow-up of 11 months, seven patients noted an emergence of symptoms between 8:00 a.m. and 11:00 a.m. When four patients were taken off the sustained-release formulation, the morning symptoms were relieved. Upon reintroduction of the bedtime sustained-release formulation, the symptoms reemerged within 15 days. A change to the use of the sustained-release formulation twice daily in these four patients was associated with relief of morning and nocturnal symptoms at a 4.5-month mean follow-up.
Augmentation is defined as a change in RLS symptoms after beginning therapy. This change includes symptoms developing earlier in the day, earlier symptom onset when at rest, increased severity of symptoms, or shorter relief of symptoms following a medication dose. Some authors suggested that 50-85% of patients receiving levodopa will develop augmentation, with an increased risk if the patient receives more than 200 mg of levodopa daily.[51,81] One case series of 51 RLS patients treated with carbidopa-levodopa demonstrated increased risk for augmentation associated with higher dose, female gender, and disease severity; augmentation was always identified within two months of treatment initiation.[83] Augmentation is usually treated by either changing to a different medication or giving doses earlier during the day.[51]
Dopamine Agonists
Dopamine agonists have been used extensively in RLS. The three agents that have the most clinical evidence are pergolide, pramipexole, and ropinirole.[84] These agents all interact with the D2- and D3-receptors; however, pramipexole has a much greater affinity for the D3-receptor than the D2-receptor. Pramipexole also has action at the D4-receptor. Pergolide has some effect on the noradrenaline receptors and the serotonin receptors, while pramipexole and ropinirole have very little to no activity at these receptors. Cabergoline and rotigotine have also been studied for RLS.
Dopamine agonists have the advantage of a longer half-life than levodopa, eliminating the concerns about the limited duration of effect through the sleeping period. While the occurrence of augmentation is generally considered to be less with dopamine agonists than with levodopa, augmentation still occurs with these agents. In general, the doses used for treatment of RLS are much smaller than the doses used to treat Parkinson's disease.
Ropinirole. Ropinirole is the first medication to receive Food and Drug Administration (FDA)-approved labeling for use in RLS. Four multi-centered, placebo-controlled trials of essentially similar design have been conducted.[85,86,87,88] Additional data from three smaller, placebo-controlled studies,[89,90,91] an open-label trial,[92] and a case series also support the use of ropinirole in RLS.[93]
In the multicentered trials, RLS patients received either oral ropinirole or placebo. Importantly, the studies excluded patients with augmentation or end-of-dose rebound with previous medications. Subjects were initially given ropinirole 0.25 mg (as the hydrochloride salt) or placebo before bedtime. Dose increases occurred every week in subjects still experiencing RLS symptoms to a maximum of 4 mg. Participants continued on treatment for 12 weeks. Efficacy was evaluated with the International Restless Legs Syndrome (IRLS) scale, the Clinical Global Impression-Improvement (CGI-I) scale, and patient report. The Walters et al.[85] study enrolled 267 subjects whose mean ropinirole dosage at the end of 12 weeks was 1.5 mg/day. The mean change in IRLS score was greater for the ropinirole group (-11.2) than for the placebo group (-8.7) (p = 0.0197). Subjects given ropinirole also improved on the CGI-I scale compared to placebo (59.5% versus 39.6%, p = 0.001). Median time for a response on the CGI-I scale was 14 days. Improvements in sleep and quality of life were also recorded. Adverse effects were more common in the ropinirole group, but fewer than 10% of subjects discontinued treatment because of them. The most common adverse effects in the ropinirole group were nausea (39.7%), headache (22.1%), fatigue (15.3%), dizziness (15.3%), upper-respiratory tract infection (13.7%), and vomiting (12.2%); no augmentation was reported.
The second study enrolled 284 subjects with RLS whose final mean dosage of ropinirole was 1.90 mg/day.[86] Again, the mean change in the score of the IRLS scale was greater for the ropinirole group (-11.04) than the placebo group (-8.03; p = 0.0036). Using the CGI-I scale, more patients in the ropinirole group (53.4%) than the placebo group (40.9%; p = 0.0416) ranked themselves much or very much improved. Subjects began to respond after the first week of ropinirole treatment: sleep improved and there was a statistically significant improvement in quality of life as assessed by the Restless Legs Syndrome Quality of Life (RLSQoL) questionnaire; no augmentation was reported. Similar adverse effects and withdrawals were seen in this study: nausea (37.7%), headache (19.9%), and somnolence (12.3%).
The third study also evaluated efficacy with polysomnograms and the Medical Outcomes Study (MOS) sleep scale in the 59 RLS subjects enrolled.[87] The final mean dosage of ropinirole was 1.80 mg/day. The number of PLMS per hour decreased significantly in the ropinirole group (48.5 to 11.8) compared to the placebo group (35.7 to 34.2; p < 0.0001). Overall, there were no statistically significant differences in the MOS sleep scale and IRLS scale between the groups with the exception of adequacy of sleep, which favored ropinirole (p = 0.0315). Ropinirole was associated with headache (34.4%), nausea (31.3%), dizziness (18.8%), and somnolence (15.6%). Augmentation was seen in 12.5% of patients treated with ropinirole.
In the fourth study, Bogan et al.[88] enrolled 380 subjects with RLS. These individuals achieved a final mean ropinirole dosage of 2.1 mg/day. The mean score on the IRLS scale decreased more for the ropinirole group (-13.6) than for the placebo group (-9.7; p < 0.001). More of the subjects treated with ropinirole were considered improved on the CGI-I scale (73.3%) than placebo-treated subjects (56.5%; p < 0.001); mean time for this improvement with ropinirole was seven days. Subjects also improved on the RLSQoL questionnaire when taking ropinirole compared to placebo (p = 0.003). Nausea, somnolence, dizziness, and vomiting were reported more frequently in the ropinirole group than in the placebo group.
Pergolide. Oral pergolide has also been used successfully to treat patients with RLS. Four placebo-controlled trials and a study in which pergolide was compared to levodopa support the use of pergolide.[94,95,96,97,98,99] Only two of these studies enrolled more than 20 subjects and will be discussed in depth.[94,95,96] In the study by Trenkwalder et al.,[94] 100 RLS patients were given pergolide or placebo for six weeks. Patients were evaluated by polysomnography, the IRLS scale, and the patient and CGI-I scales. Sixty-eight percent of pergolide-treated subjects were considered responders in this trial. Final mean pergolide dose was 0.40 mg (as the mesylate salt) per day. The PLMS arousal index, defined as the number of PLMS with arousals per hour of total sleep time, decreased with pergolide treatment (mean 15.2 at baseline versus 2.6 after six weeks of treatment; p = 0.004). Compared to placebo, the pergolide group had a better (decreased) PLMS arousal index (p < 0.001), enhanced IRLS score (p < 0.001), and improvement on the CGI-I scale (p < 0.001). Nausea and headaches occurred more frequently in those patients treated with pergolide. All subjects in this trial were given the opportunity to participate in an open-label, one-year extension of pergolide treatment. Beneficial effects were maintained to the one-year point, at which time the mean dosage was 0.52 mg/day. Augmentation was not reported.
A crossover study of pergolide and placebo was conducted with 28 RLS patients.[95] These subjects were assessed with polysomnography, the Standardized Sleep Inventory SF-A, a quality-of-life questionnaire, and sleep diaries. Of note, patients were treated with domperidone 20 mg p.o. three times daily during the entire 12-week study and one-year open-label follow-up period to prevent nausea. The final mean pergolide dose was 0.51 mg/day. Pergolide was associated with statistical improvements in PLMS (p < 0.0001), total sleep time (p = 0.0001), reported sleep quality (p = 0.0001), and life satisfaction (p < 0.0001). Following completion of the double-blind study, these subjects were followed for one year in an open-label fashion.[96] Six participants discontinued pergolide during the year. The mean dosage at the end of the year was 0.37 mg daily. Augmentation developed in six patients; however, none required additional dosing.
Adverse effects of pergolide when used for RLS include nausea, headache, and rhinitis.[95] Augmentation has been reported in 15-27% of pergolide-treated subjects.[97,100] Pergolide's use has been significantly curtailed following reports of valvular heart disease in patients with Parkinson's disease treated with the drug.[101] A case of pleuropulmonary disease has also been reported following pergolide use for RLS, indicating that its ergot-related adverse effects are not limited to its use in Parkinson's disease.[102]
Pramipexole. Fewer studies have been conducted with pramipexole; only one double-blind, placebo-controlled, crossover trial of 10 subjects exists.[103] Pramipexole was associated with a 98% decrease in PLMS (p = 0.01); however, 90% of the subjects reported gastrointestinal adverse effects (nausea, constipation, or loss of appetite) when taking pramipexole. Seven of these patients were followed for an additional mean of 7.8 months with no reports of augmentation.[104] Six subjects achieved a final pramipexole dihydrochloride dosage of 1.5 mg/day while four subjects took 0.75 mg/day. Sixty patients who had been prescribed pramipexole for RLS were examined in a retrospective fashion; of these, 67% found pramipexole completely effective, 27% partially effective, and 7% received no benefit.[105] Adverse effects were reported by 40% of patients, including insomnia (13%) and nausea or dyspepsia (12%). Eleven patients stopped pramipexole dihydrochloride within 4 months of initiation; the remaining 49, taking a median dosage of 0.63 mg/day, were followed for an average of 27.2 months. Augmentation developed in 33% of patients taking pramipexole for two years.
Prolonged Therapy. There is a report of a series of patients given a variety of dopamine agonists for longer treatment times. A retrospective study of patients placed on pramipexole (n = 52), ropinirole (n = 19), or pergolide (n = 12) for at least six months showed maintained efficacy.[106] However, slight augmentation requiring an earlier onset of treatment occurred in 48.2% of patients. More severe augmentation was seen in 21.7% of patients. The long-term effects of dopamine agonists were also analyzed retrospectively in these same 83 patients who had at least 6 months (mean, 39.2 months) follow-up data. Adverse effects were reported by 56.7% of subjects and included daytime sleepiness (26%), nausea (13%), peripheral edema (13%), dizziness or light-headedness (5%), gastrointestinal upset (4%), constipation (3%), headache (3%), itchiness (2%), and rash (2%). Additional RLS medications were required by 19.3% and augmentation was seen in 71% of participants. Lack of neuropathy was predictive of augmentation.
Other Dopamine Agonists. Cabergoline efficacy was assessed with the Restless Leg Syndrome-6 (RLS-6) scale in a randomized, double-blind, placebo-controlled, multicenter, dose-finding trial of 98 RLS subjects.[107] Improvement was noted in all dosing groups (0.5, 1, and 2 mg p.o.) of cabergoline when compared with placebo, with the most improvement seen in the 2-mg group (p = 0.0026). Nausea was the most prominent adverse effect seen in the cabergoline-treated groups. Six patients (9.1%) developed augmentation over 47 weeks.
The labeling for rotigotine, a patch-formulation dopamine agonist, has not yet been approved by FDA in the United States. In a pilot study with a treatment duration of one week, three dosages (1.125, 2.25, and 4.5 mg/day) of rotigotine patches were compared with placebo in 63 moderate-to-severe RLS patients.[108] Efficacy was evaluated by the IRLS, RLS-6, and CGI-I scales. There was a decrease on the IRLS scale of 15.7 points in the group given 4.5-mg/day compared to 8.0 points in the placebo group (p = 0.0095). On the CGI-I scale, 89.5% of the 4.5-mg group was much or very much improved versus 42.9% in the placebo group (p = 0.0119). Adverse effects to rotigotine included the following: 26.5% had application-site reactions, 22.4% had headaches, 22.4% developed pruritus, and 6.2% had nausea.
While dopaminergic agents have demonstrated the ability to effectively treat RLS, a need still exists for other types of medications. Many patients develop nausea with dopaminergics. In addition, augmentation is a significant problem in this class of agents, whether using levodopa or dopamine agonists.
Anticonvulsants
Several of the oral anticonvulsants have been used to treat RLS. The three medications with evidence from placebo-controlled studies are gabapentin, carbamazepine, and valproic acid. These three agents all augment γ-aminobutyric acid (GABA), which may, in turn, inhibit impulse transmission at the spinal cord level. Additionally, GABA may play a role in dopamine and serotonin release, which could affect RLS in an as yet undescribed fashion.[109,110,111]
Four small, randomized, double-blind trials with gabapentin have been conducted.[109,112,113,114] Only the one that enrolled more than 20 subjects will be discussed. This placebo-controlled, crossover, six-week study enrolled 24 RLS patients and assessed symptom improvement using the IRLS scale, the Clinical Global Impression of Change (CGIC), and the Pittsburgh Sleep Quality Index.[109] Subjects given gabapentin improved on the IRLS scale (p < 0.0005) and the CGIC (p < 0.0001) but not the Pittsburgh Sleep Quality Index compared with placebo. The final mean dosage of gabapentin was 1855 mg/day. Adverse effects that occurred in more than one subject in the gabapentin group included malaise and somnolence. No augmentation was seen.[109]
The following three studies evaluated carbamazepine for RLS: a small open-label trial,[110] a small placebo-controlled study,[115] and a large placebo-controlled study.[116] In the large study, 174 RLS patients were given either carbamazepine, at a final median dosage of 236 mg/day, or placebo.[116] Visual analogue scales were used to record severity of symptoms and therapeutic effects. The number of RLS episodes was decreased in the carbamazepine group as recorded in subject diaries (p = 0.03). The therapeutic effect was significant in carbamazepine-treated subjects (p < 0.01), and the severity of symptoms was improved in the carbamazepine group compared with placebo (p < 0.01).
Twenty subjects were included in a double-blind, crossover trial of placebo, extended-release valproic acid 600 mg p.o., and slow-release benserazide 50 mg with levodopa 200 mg p.o.[111] Subjects documented the frequency, duration, and severity of their RLS symptoms as the primary outcome. Valproic acid mitigated the intensity and duration of symptoms compared to levodopa. Most of this symptom improvement occurred between midnight and 8 a.m. Levodopa worked well between midnight and 4 a.m., but subjects had a nonsignificant increase in RLS symptoms between noon and midnight.[111]
Of the anticonvulsants, the most convincing evidence for efficacy in RLS is for carbamazepine due to the size of the Telstad et al.[116] study. However, gabapentin also appears promising, and adverse effects are reported considerably less often with gabapentin than with carbamazepine in the treatment of epilepsy. In addition, fewer drug-drug interactions occur with gabapentin compared to either carbamazepine or valproic acid. Not enough data exist to compare the adverse-effect profiles of these agents when used to treat RLS. Although gabapentin and carbamazepine have short half-lives, no augmentation has been reported with any of the anticonvulsant agents.
Opioids
Opioids are often used for RLS, but the evidence to support their effectiveness is not robust. Propoxyphene and oxycodone are the only agents that have been studied in small, controlled trials.[117,118] Both of these agents reduced PLMS associated with arousal. Tramadol has also been examined in an open-label fashion and judged by patients to be more effective than their previous treatments.[119] Adverse effects and dependence issues may also limit the role of opioids in the treatment of RLS.
Benzodiazepines
Of the benzodiazepines, clonazepam is the most frequently studied medication. Clonazepam has been compared to placebo in three small studies[120,121,122] and to temazepam in a single small study.[123] Only three of these studies support the use of clonazepam in RLS.[120,122,123] The largest trial enrolled 10 RLS patients and 16 PLMD patients who underwent a one-dose, single-blind, placebo-controlled, crossover study of clonazepam 1 mg p.o.[120] Subjects were evaluated by polysomnography and the Self-Assessment of Sleep and Awakening Quality scale. Subjective sleep quality improved with clonazepam compared with placebo (p < 0.025), and clonazepam-treated participants also experienced decreased time awake and number of awakenings.
Am J Health Syst Pharm. 2006;63(17):1599-1612. © 2006 American Society of Health-System Pharmacists
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