Dopaminergic Therapy of Restless Legs Syndrome

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Chapter 31 Dopaminergic Therapy of Restless Legs Syndrome

Since Akpinar’s original 1982 report1 on the dramatic effects of levodopa on restless legs syndrome (RLS) symptoms, there have been numerous, independent studies that have validated these findings and that have substantially verified the effectiveness of all dopaminergic agents in treating RLS. However, despite current research supporting the notion that dopaminergic agents represent the most effective agents for treating RLS, the dopaminergic agents do have their limitations and have not turned out to be the long-term panacea that RLS patients had hoped for. However, at the current time there is no other class of agents that can be said to be as consistently and broadly effective (>90% efficacy) as the dopaminergic agents. In this chapter, the relevant pharmacology of the dopaminergic drugs, the research support for treatment efficacy, management issues, and side effect profiles are discussed.

Pertinent Pharmacology of Dopaminergic Agents

For more details about the biochemical basis of dopaminergic neuropharmacology, which is relevant to understanding the actions of the drugs to be discussed below, see Chapter 11. The effects of the various dopaminergic medications reflect both their kinetics of uptake and elimination and their relative effects on the dopaminergic system. These are presented in Table 31-1 for each of the dopaminergic medications currently used to treat RLS. Levodopa is taken up by the dopamine producing cells and decarboxylated into dopamine adding to the dopamine produced in the cells available for release. Because the feedback mechanisms regulating dopamine production and release do not respond to levodopa, the drug has little immediate effect until after it is converted into dopamine, which potentially activates all five of the dopamine receptors. The dopamine agonists act on the dopamine receptor and differ in terms of relative affinity for each of the five dopamine receptors. Because the medications currently used to treat RLS all activate D2 receptors, they also activate the presynaptic autoreceptors serving to decrease dopamine production and release. This presynaptic activation may predominate at lower doses or initially after taking the medication. All the dopamine agonists currently used for the treatment of RLS have D2 and D3 activation, but only pergolide has significant D1 activation.

The major kinetic difference among the dopamine medications involves half-lives that vary from very short (1 to 2 hours) for levodopa and rotigotine to intermediate (4 to 8 hours) for ropinirole and pramipexole to long for pergolide (10 to 12 hours) and very long for cabergoline (60 hours). These provide some relative guideline for the duration of efficacy of the medication. Time to reach maximum blood levels varies from fairly rapid for levodopa and ropinirole (1 hour) to intermediate for pramipexole and pergolide (2 hours) and somewhat longer for cabergoline (3 hours). The rotigotine patch when worn as directed with repeated replacement every 24 hours provides fairly constant blood levels, which drop rapidly when the patch is removed. These provide some information on relative times from taking the medication to experiencing treatment benefit.

Dopaminergic Medications for the Treatment of Restless Legs Syndrome

Levodopa in Restless Legs Syndrome

Levodopa was first reported as a treatment for RLS in 1982.1 Since then, 10 double-blind crossover controlled trials of levodopa with a dopa decarboxylase inhibitor have been reported, two studying the effect of the medication on RLS alone,2,113 four on PLMS alone,47 and four on both.811 One study included only uremic patients,7 one study included only narcoleptics,4 two studies included patients with either uremic or idiopathic RLS,8,12 and the remaining six studied patients with idiopathic RLS. Of these, five trials have had a sample size of eight or fewer,4,5,7,9,113 two had a sample size of 10 to 20,2,6 and three had a sample size of 30 to 32 patients.8,10,12 Despite the low power of most of the studies, all showed benefit for the drug over placebo in at least some parameters. RLS symptoms were assessed subjectively in different ways, but all studies showed a statistically significant benefit of levodopa over placebo. In the largest published study,8 physician ratings of RLS severity at sleep onset improved 77% over baseline with 100 to 200 mg levodopa at bedtime compared with 36% improvement with placebo, while ratings of RLS during the night improved 57% compared with 11% with placebo. Periodic limb movement indices (PLMI) also improved significantly with the drug (47% improvement over baseline compared with a 7% worsening with placebo).8 However, this effect was restricted to the first half of the night when immediate-release levodopa was administered before sleep. A significant beneficial effect of levodopa was demonstrated on the first night of use, thus allowing for the drug to be used intermittently. One study examined the effects of administering a combination of immediate release and slow release levodopa before sleep to patients with persistent symptoms in the second half of the night.10 The quality of sleep, intensity of RLS, and PLMI significantly improved in the second half of the night with the combination compared with immediate-release levodopa alone. The effects on objective sleep measures have been more varied, with contradictory effects reported on sleep latency and percentage slow wave sleep.5,6,11 Frequent episodic K-alpha complexes have been noted to commonly occur with PLM and these persist unchanged despite reduction in PLMI with levodopa.7

Long-term effects of levodopa therapy have been studied in a number of clinical series comprising 7 to 51 patients followed for 4 weeks to more than 2 years.3,1320 The percentage of patients who discontinued medication varied between 13% and 65%,3,14,19,21 depending on the duration of follow-up and the availability of alternative effective agents at the time of the study. The major problem encountered was daytime augmentation (Table 31-2). This occurred in 82% of 30 patients with RLS treated with a mean of 267 mg levodopa followed for at least 2 months.13 Of 33 levodopa failures in a study of 51 patients, 85% were caused by augmentation.13 In a 1-year extension of a controlled trial of immediate- and slow-release levodopa, 8 of 23 patients discontinued the drugs because of augmentation and RLS severity during the day increased in an unspecified number of the remainder.19 Factors increasing the risk of augmentation include a dose of 200 mg or more levodopa and the onset of RLS symptoms before 6 P.M. before medication.13 A minority of patients with PLMS alone treated with levodopa will develop RLS earlier in the day.13 If augmentation is treated with additional doses of levodopa earlier in the day, further augmentation often occurs, sometimes with catastrophic increases in symptoms.13 Except for mild cases, levodopa should be discontinued if augmentation develops and a dopamine agonist or other class of medication introduced.

TABLE 31-2 Criteria for Clinical Diagnosis of Augmentation

A. Basic features (all of which need to be met)

In addition, either B or C or both have to be met: B. Persisting (although not immediate) paradoxical response to treatment: RLS symptom severity increases some time after a dose increase, and improves some time after a dose decrease OR C. Earlier onset of symptoms

Augmentation requires criteria A + B, A + C, or A + B + C to be met.

Reprinted with permission from Garcia-Borreguero D, Allen RP, Kohnen R, et al. Diagnostic standards for dopaminergic augmentation of restless legs syndrome: Report from a World Association of Sleep Medicine—International Restless Legs Syndrome Study Group Consensus Conference at the Max Planck Institute. Sleep Med 2007;8:520-530.

An additional adverse effect of levodopa is that of morning rebound. This phenomenon, characterized by an increase in symptoms in the morning, may be related to the short half-life of levodopa. It occurs in 19% to 35% of patients1315 and may be more common if an additional dose of levodopa is administered during the night.13 The short duration of action of direct release levodopa and tendency to rebound effects were confirmed in a polysomnograph study: PLMS were significantly reduced in the first third of the night, but increased in the last third compared with baseline.16 The frequency of tolerance (the need for an increase in the dose with time to treat the same symptoms) is hard to determine because of the varying natural history of the disorder and the complicating effects of augmentation and rebound. Side effects from the drug were not severe in the long-term studies, with nausea, lightheadedness, and diarrhea occasionally limiting therapy.3,13,18,19

In summary, levodopa is effective in controlling RLS, but its use is severely limited by the development of daytime augmentation and morning rebound. Current guidelines suggest that its use should be limited to RLS that does not occur sufficiently frequently to require daily medication.22

Dopaminergic Agonists in Restless Legs Syndrome

These can be divided historically into ergot and nonergot agents. Those initially developed were all ergot agonists and appear to share the potentially serious, although rare, problem of systemic fibrosis and cardiac valvular pathology. The more recently developed dopamine agonists are not ergot agonists and do not carry the risk of systemic fibrosis.

Ergot Agonists

Pergolide

Four randomized, controlled trials of pergolide in the treatment of RLS have been reported, three for idiopathic RLS2426 and one for RLS in uremia.27 Sample sizes ranged from 8 to 83, and treatment duration, from 10 days to 6 weeks. The larger trials showed an improvement in RLS symptomatology of 87% over baseline compared with 13% with placebo (based on a 10-point self-rating scale at bedtime)26 and 52% compared with 7% (using the International Restless Legs Scale).25 In one study, the PLM arousal index fell from baseline by 83% compared with 20% with placebo,25 whereas another demonstrated a 93% reduction in PLM arousal index compared with placebo, sustained for 7 hours of sleep.26 Significant changes in total sleep time and sleep efficiency were noted in some studies24,26 but not in others.25,27 The average daily dose used ranged from 0.25 to 0.4 mg.

Information is available from open-label, follow-up studies of 10 to 31 patients using pergolide for a mean of 6 to 25 months.13,2833 The mean daily dose used ranged from 0.1 to 0.67 mg with the higher doses reported in studies in which domperidone was added to control nausea.3133 The percentage of patients continuing to use the drug throughout the study varied between 55% and 93%, with all but two studies32,33 reporting a range of 70% to 80%. Augmentation did occur but at a lower frequency than with levodopa. Augmentation occurred in 15% to 38% of patients in four different studies, each lasting a mean of 12 or more months.13,28,30,31 In addition, augmentation was generally mild and, unlike with levodopa, could usually be controlled with an additional dose of the drug earlier in the day.28 Like levodopa, pergolide has been reported to induce RLS when used to treat PLMS alone.34 Nausea occurred frequently (35% to 41%)28,25,26,31 but could easily be controlled by the addition of domperidone (in countries where it is available). Other side effects included orthostatic hypotension, nasal stuffiness, insomnia, constipation, and peripheral edema.

An additional potential complication of pergolide therapy is the development of ergot-related pleuropulmonary, cardiac valvular, pericardial, or retroperitoneal fibrosis.35,36 Although most frequently found in patients taking pergolide for Parkinson’s disease,115 similar complications have been reported in patients treated with higher doses of pergolide (1.5 and 3.5 mg daily) for RLS.37,38 A case control study of 46 patients on pergolide for Parkinson’s disease suggested a 2- to 3-fold increased risk of abnormal valves in the pergolide group and a 14-fold increased risk of tricuspid regurgitation.39 Other studies have shown relative risk ratios of valvulopathy in association with pergolide therapy for Parkinson’s disease of 2.3 and 7.1.40,41 Cumulative dose appears to be a risk factor for the development of valvulopathy. Pergolide was withdrawn from the U.S market in 2007; in countries where it is still available, it should be rarely prescribed and regular echocardiograms should be performed.

In summary, pergolide is a highly effective drug for the treatment of RLS. However, a high frequency of side effects, especially nausea, and concerns regarding the induction of systemic fibrosis limit its use.

Cabergoline

Cabergoline is an ergot-based dopamine agonist with an extremely long elimination half-life of 65 to 110 hours.42 It has been investigated for the treatment of RLS in three open-label trials4244 and in two multicenter double-blind placebo-controlled trials.11,45 Two of the open-label trials studied small numbers of patients (9 and 12),43,44 while the third reported on 302 patients from multiple sites.42 The duration of follow-up ranged between 3 and 12 months. All three open-label studies commenced therapy with 0.5 mg cabergoline in the evening. Mean effective doses ranged from 1.3 to 2.1 mg. The two studies using the International Restless Legs Syndrome Study Group Severity Scale (IRLS) showed a reduction of 64 and 75% in RLS severity compared with baseline.42,44 In one study using follow-up polysomnography, PLMI fell by 87%.43 In the largest study, 18% of patients discontinued the drug in the first 6 months, the majority due to side effects.42 Side effects thought to be drug related occurred in 48% of patients, the majority in the first month of therapy. Nausea was the commonest (17%), with dizziness, fatigue, and edema also noted. Possible daytime augmentation within 6 months was reported in 3%, but another much smaller study reported no augmentation at 1 year.44

In the first controlled study, 85 patients were randomly assigned to one of four treatment conditions: placebo and 0.5, 1.0, and 2.0 mg of cabergoline taken once daily. Dose was titrated up over the first 2 weeks of the study and then held constant until week 5 at which point efficacy was evaluated using the validated IRLS.46 Patients were then entered into a longer-term (48 weeks) open-label trial with 6 weeks of dose adjustment to efficacy and then maintained for 42 weeks. In the double-blind phase, the average IRLS score decreases from baseline were 3.3 for placebo and 13.1, 13.5, and 15.7 for doses of 0.5, 1.0, and 2.0 mg (approximately 43% to 55% decreases). Both the 1- and the 2-mg doses produced statistically significant improvement compared with placebo (P <.05) but not the lowest dose (P >.05). The number of adverse effects were low and only nausea occurred appreciably more often than for placebo. Augmentation occurred in about 9% of those continuing in the long-term open-label study.45

In the second controlled trial conducted in 51 European centers,11 Cabergoline at fixed doses of 2 or 3 mg/day was compared with levodopa at doses of 200 or 300 mg/day over a 30-week period. The primary outcome measure was the IRLS, which declined by 16.1 points in the cabergoline group (n = 178) and by 9.5 points in the levodopa group (n = 183). More patients in the levodopa than the cabergoline group dropped out due to loss of efficacy (14.2% versus 7.9%) or augmentation (9.8% versus 4.0%), the second primary end point. More side effects occurred in the cabergoline group, such as gastrointestinal symptoms (55.6% versus 30.0%), and the authors concluded that cabergoline was not as well tolerated.

In a third controlled trial that focused on polysomnography,47 the PLMS-associated arousal index decreased and the sleep efficiency increased compared with placebo. Subjective measures, including IRLS, QoL-RLS, and RLS-6 day and night measures, were all improved as well.

Fibrosing reactions were not evaluated in these studies; cabergoline, nonetheless, like pergolide, has been associated in high doses with occasional ergot-related systemic fibrosis.48,49 Studies of cabergoline in Parkinson’s disease have shown relative risk ratios of 1.7-12.96 for the occurrence of cardiac valvulopathies.40,41,50 The dose range associated with valvulopathy was 2 to 7 mg in one study with total cumulative dose being a risk factor.50 If cabergoline is used for RLS, regular echocardiograms are essential.

In summary, cabergoline provides another dopaminergic agonist in the treatment of RLS. Of special interest is its long half-life, which may result in a lower incidence of augmentation. However, ergot-type side effects limit its use.

Alpha-dihydroergocryptine

A single 4 week open-label trial of alpha-dihydroergocryptine (DHEC) in 16 patients has been reported,51 with results similar to those seen with other ergot-based agonists. The dose was titrated from 5 mg daily to a mean of 23 mg daily. Using a visual analogue scale, RLS severity at night fell by 64% from baseline. Side effects were noted in 87% of patients, predominantly nausea. No augmentation was noted over the short duration of the study.

Terguride

A single 2- to 8-week open-label study of nine patients receiving terguride (transdihydrolisuride) for RLS has been reported.54 The effective dose range was 0.25 to 0.5 mg daily. One patient discontinued the drug due to abdominal pain and one developed augmentation. The IRLS fell by a mean of 42% from baseline.

Nonergot Agonists

Pramipexole

Extensive randomized, double-blind placebo controlled trials of pramipexole in RLS have been undertaken and these have been reviewed by the U.S. Food and Drug Administration, which in 2006 approved the use of pramipexole for treatment of moderate to severe RLS. Two large (N = 344 or 345) double-blinded, placebo-controlled trials evaluated efficacy and safety of pramipexole treatment of primary RLS with a randomization giving twice as many subjects on pramipexole as placebo. Both studies used the clinical global improvement and the change from baseline in IRLS as primary end points. One study conducted in Europe110 with individually titrated doses ranging from 0.125 to 0.75 (median pramipexole dose of 0.35 mg/day) reported response after 6 weeks of treatment. The mean IRLS score decreases were 5.7 for placebo and 12.3 for pramipexole. The percentage much/very much improved was 32.5% on placebo and 62.9% on pramipexole. In the second study conducted in the United States,114 patients were randomized to placebo or one of three fixed pramipexole doses of 0.25, 0.5, and 0.75 mg/day. Responses evaluated after 12 weeks of treatment showed decreases on the IRLS of 9.3 for placebo versus 12.8 for 0.25 mg, 13.8 for 0.5 mg, and 14.1 for 0.75 mg doses. The percentage much/very much improved on the CGI was 51.2% for placebo vs. 74.7% for 0.25, 67.9% for 0.5 mg and 72.9% for 0.75 mg.33 This study showed significant improvement in the IRLS for the 0.5 compared with the 0.25 mg dose but there was no significant added treatment benefit for the highest dose of 0.75 mg. In another study, 150 RLS patients who had responded to pramipexole were randomly switched to either placebo or continuing on their pramipexole and followed for another 3 months. The percentage of patients with predefined worsening of RLS scale and also a decrease in Clinical Global Improvement was 85.5% for placebo and 20.5% for pramipexole treatment.56 A third study was a dose-finding parallel-group polysomnography study in which a total of 109 patients were randomly administered one of the following: placebo, 0.125 mg, 0.25 mg, 0.5 mg, or 0.75 mg for 3 weeks. The PLMI was reduced in all four drug groups by about 80% compared with placebo. The IRLS was lower for all drug doses compared with placebo, with the higher doses showing more than 50% reduction.57 In these three larger trials, pramipexole was well tolerated with the usual adverse effects for a dopamine agonists (mostly nausea).

At least 10 open-label studies of pramipexole treatment of RLS have been reported.5866108 The four largest studies included 52 to 195 patients each with mean follow-ups of 21 to 39 months.61,62,65,66 In three studies, between 37% and 76% of these patients had received prior levodopa, whereas in the largest,66 no patient had received prior dopaminergic therapy. The mean dose after initial stabilization for most patients was in the range of 0.3 to 0.6 mg daily. Efficacy was assessed using various quantitative measures. In one study, 94% of patients reported a partial or complete response,62 while another demonstrated a 75% improvement on a physician’s global impression scale.65 Side effects, although common, were generally mild and self limited and only occasionally led to discontinuation of the drug. Nausea, insomnia and lightheadedness were the most common, although edema and nasal congestion were occasionally described. Peripheral edema, reversible on discontinuation of the drug, has been reported to occur in about 17% of patients taking pramipexole, predominantly in high doses for Parkinson’s disease.67 Sleepiness is uncommon in RLS patients treated with pramipexole62,63

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