Elsevier

Sleep Medicine

Volume 5, Issue 1, January 2004, Pages 9-14
Sleep Medicine

Original article
Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome (RLS)

https://doi.org/10.1016/j.sleep.2003.07.005Get rights and content

Abstract

Background: Dopaminergic agents have become first-line treatments for restless legs syndrome (RLS). The most common serious complications of l-Dopa treatment of RLS are ‘augmentation’, in which RLS symptoms appear earlier during the day, and tolerance, in which medication effectiveness wanes over time. The aims of this study were to assess rates of augmentation and tolerance, and their interrelationship, with pramipexole treatment of RLS.

Patients and methods: Retrospective assessment of all patients (N=59) treated for RLS with pramipexole for at least 6 months (mean duration=21.2±11.4 months) by the senior author. Pramipexole dosing and clinical follow-up were performed in a standardized fashion. l-Dopa was discontinued and other medications for RLS were tapered as tolerated. Rates of augmentation (need for earlier administration of the same dose of pramipexole) and tolerance (need for an increase in pramipexole dose) were determined.

Results: Augmentation developed in 32% (19/59), and tolerance occurred in 46% (27/59), of patients. These two complications were statistically related (P<0.05). The only clinical predictors of these complications were previous augmentation or tolerance to l-Dopa.

Conclusions: Augmentation and tolerance are more common with extended pramipexole treatment of RLS than has been previously reported in preliminary studies. However, these complications are generally manageable by earlier dosing or small dose increases of this agent, and only rarely require medication discontinuation.

Introduction

Restless legs syndrome (RLS) is a sensory-motor disorder consisting of dysesthesia and an abnormal urge to move the legs, predominantly during the evening and night time. It interferes with activities requiring immobility, most prominently, sleep. Dopaminergic precursors (e.g. l-Dopa) and agonists (e.g. pramipexole, ropinirole, pergolide) have become first-line treatments for RLS over the past 10 years due to their extraordinary effectiveness in reducing these primary symptoms as well as periodic leg movements during sleep [1]. However, due to concerns regarding complications of l-Dopa, the longer acting dopaminergic agonists have superseded this agent as the primary treatment for RLS.

The most common serious complication of l-Dopa treatment of RLS is ‘augmentation’, in which RLS symptoms appear earlier during the day, or less commonly, extend beyond the originally affected limbs [2]. Augmentation occurs in nearly 70% of those given l-Dopa for RLS [3] and can at times be quite severe, with patients' increasing the number and strength of l-Dopa doses and ending up with increasingly severe symptoms throughout the day. Previous reports suggest that the dopaminergic agonist pergolide less commonly produces augmentation than l-Dopa in the treatment of RLS [3], [4], [5], [6].

The rate of augmentation with the newer dopaminergic agonists, ropinirole and pramipexole, is not well defined, though preliminary reports are available. Montplaisir [7] followed seven patients on pramipexole (mean dose=0.5 mg) for a mean of 7.8 months and found continued benefit of this agent, without augmentation. Similarly, Ferini-Strambi [8] found that only 9 of 102 patients (9%) with RLS, followed for at least 6 months, had augmentation with pramipexole (mean dose=0.4 mg). In both patient populations, pramipexole was given as a single dose at bedtime. On the other hand, Silber [9] described 50 patients treated with pramipexole for RLS who were followed for a mean of 13.1 months, nearly all of whom had failed previous dopaminergic treatment. Augmentation occurred in 18% of these patients at a mean duration of 8.5 months (range 2–16 months). Nearly two-thirds of those with augmentation to pramipexole had developed this complication with either l-Dopa or pergolide. In general, augmentation was easily managed by earlier medication dosing.

Another potential complication of long-term medication treatment is the need for larger doses of medication to maintain the original effect (tolerance). Earley and Allen [3] documented an increase in l-Dopa dose in 59% of patients with RLS followed for an average of 21 months. However, it is unclear from their data whether the l-Dopa dose was increased due to the development of augmentation or due to tolerance. It is unknown whether tolerance to the direct dopaminergic agonists develops or whether this process is related to that of augmentation for these agents. Defining the frequency of tolerance, and its relationship to augmentation, for dopaminergic treatments in RLS may be of value in understanding the physiology of therapeutic action of these agents. In addition, tolerance is a frequent concern of patients and physicians.

The aims of this study were to assess the long-term effects of pramipexole in the treatment of RLS. In particular, we were interested in the rates of augmentation and tolerance, and their interrelationship, with this agent.

Section snippets

Methods

Charts were reviewed for 72 consecutive patients begun on pramipexole treatment for RLS by the senior author. An RLS diagnosis was confirmed if the following criteria, established by the International Restless Legs Syndrome Study Group [10], were met: an urge to move the limbs, particularly the legs, usually associated with dysesthesia; motor restlessness; symptoms are worse with immobility and improve with movement; symptoms initially appear or worsen in the evening or at night. In addition,

Results

Fifty-nine patients met inclusion criteria (see Table 1). Mean age was 60.8 years (±14.4; range 31–91); 34 were female (58%), 25 were male (42%), 58 were Caucasian and 1 was Asian. Thirteen of the patients (22%) had secondary RLS (8 neuropathy, 2 end-stage renal disease, 1 Parkinson's, 1 anemia, 1 multiple sclerosis). Twenty percent (12/59) had a family history of RLS in a first-degree relative. The mean PLMS index was 46.6 (±40.0) and the mean PLM arousal index was 14.7 (±17.6).

Stable baseline

Discussion

This naturalistic case series provides the first detailed description of a large group of patients treated with pramipexole long-term for RLS. We found a rate of augmentation (32%) requiring earlier pramipexole administration, which was higher than that had been preliminarily reported for this agent, though similar to that described for pergolide, another dopaminergic agonist. What could account for this disparity between our results and those of others using pramipexole? Given Allen and

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