Preamble
Augmentation is a worsening of RLS symptom severity experienced by patients undergoing treatment for RLS. The RLS symptoms in general are more severe than those experienced at baseline
A. Basic features (all of which need to be met):
1. The increase in symptom severity was experienced on five out of seven days during the previous week
2. The increase in symptom severity is not accounted for by other factors such as a change in medical status, lifestyle, or the natural progression of the disorder
3. It is assumed that there has been a prior positive response to treatment
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:
1. An earlier onset by at least four hours
OR
2. An earlier onset (between two and four hours) occurs with one of the following compared to symptom status before treatment
a. Shorter latency to symptoms when at rest
b. Spreading of symptoms to other body parts
c. Intensity of symptoms is greater (or increase in periodic limb movements [PLM] if measured by polysomnography [PSG] or the suggested immobilization test [SIT])
d. Duration of relief from treatment is shorter
Augmentation requires criteria A + B, A + C, or A + B + C to be met
Several studies have reported a correlation between the presence of augmentation during dopaminergic treatment with the severity of RLS/WED symptoms at baseline and with a higher medication dosage, but not with age or gender [8–10]. Clinical experience shows that when severe, augmentation can result in a weakening or even a loss of essential RLS/WED features. Thus, symptoms are no longer reduced during inactivity or movement, and there is virtually no circadian pattern. The clinical picture obtained during dopaminergic augmentation resembles the one obtained in severe RLS/WED, with severe symptoms occurring most of the day and affecting all limbs. None of the clinical features of dopaminergic augmentation are specific to this condition or can be differentiated from RLS/WED itself. In fact, RLS/WED augmentation reflects a worsening of RLS/WED severity during dopaminergic treatment. Recently published recommendations on the management of augmentation from the International RLS Study Group (IRLSSG) identified a number of screening questions that may be used in clinical practice to identify possible augmentation, but these have yet to be validated [11].
Incidence of Augmentation Under Dopaminergic Agents
Dopaminergic augmentation is very common and mostly unidentified in everyday clinical practice. A community survey performed on 266 RLS/WED patients being treated by primary care physicians or neurologists in the USA, whose medical records were reviewed by independent experts, showed some degree of augmentation in 75% of patients (20% with definite augmentation and 55% had partial symptoms of augmentation) [12].
A number of studies claim to have evaluated the incidence of augmentation for different drugs either prospectively or retrospectively (See Table 12.2). However, several issues make it difficult to ascertain correct incident rates for the different treatments for RLS/WED: Firstly, as mentioned above, there was no operational definition for augmentation before 2002. Secondly, the estimation of augmentation rates has been performed retrospectively, using different diagnostic criteria, and frequently based on the evaluation of clinical cases. Studies were not specifically designed to measure augmentation and frequently lacked specific information on augmentation. Third, trials were frequently not long enough for augmentation to manifest: It is a long-term consequence of treatment, and therefore, trials need to be longer than 6 months for augmentation to be seen. Finally, there is a lack of comparative trials with one single exception [4].
Study | Design | Duration | Sample size | Assessment | Incidence of augmentation |
|---|---|---|---|---|---|
Levodopa | |||||
Allen 1996 [5] | Prospective case series | N/A | 30 | Increase in appearance and severity of RLS/WED symptoms | 73.3% (22/30 patients) |
Trenkwalder 2007 [21] | Double-blind, randomized, active-controlled (cabergoline) trial | 30 weeks | Levodopa: 183 Cabergoline: 178 | ASRS ≥ 1 Augmentation defined according to NIH criteria | Augmentation (ASRS ≥ 1) Levodopa: 40.4% Cabergoline: 21.1% Discontinuations due to augmentation Levodopa: 9.8% (18/183 patients) Cabergoline: 4.0% (7/178 patients) |
Hogl 2010 [22] | Open-label trial | 6 months | 60 | Augmentation diagnosed by two experts using established criteria. Changes in ASRS, IRLS, and CGI were analyzed | Augmentation: 60% (36/60 patients) Discontinuations due to augmentation: 11.7% (7/60 patients) |
Rotigotine | |||||
Trenkwalder 2008 [23] | Double-blind, randomized, placebo-controlled trial | 6 months | Rotigotine: 341 Placebo: 117 | ASRS (4-item version) | No signs of augmentation noted |
Hening 2010 [24] | Double-blind, randomized, placebo-controlled trial | 6 months | Rotigotine: 405 Placebo: 100 | ASRS (4-item version) Retrospective analysis of study data by an expert panel using the MPI criteria | Clinically relevant augmentation: 1.5% (6/404 patients) on rotigotine 1% (1/100 patients) on placebo |
Oertel 2011 [25] | Open-label, continuation of double-blind, randomized, placebo-controlled trial | 5 years | 295 | ASRS Retrospective analysis of study data by an expert panel using the MPI criteria | Clinically significant augmentation: 5% (15/295 patients) on EMA-approved dosea |
Benes 2012 [26] | DB: 6 months OL: 12 months | DB: rotigotine, 745; placebo, 214. OL: 620 | Expert review of study data (IRLS, RLS-6, CGI-1, ASRS) using the MPI criteria | Clinically relevant augmentation DB: 1.5% (11/745 patients) on rotigotine; 0.5% (1/214) patients on placebo OL: 2.9% (18/620 patients) | |
Cano 2013 [28] | Retrospective chart review | 12 years | 138 (112 received ≥1 RLS/WED medication) | Not specified | Rotigotine: 0% Clonazepam: 37.1% Ropinirole: 40.4% |
Inoue 2013 [29] | Open-label continuation of a double-blind trial | 1 year | 185 | ASRS ≥ 5 used to identify patients with possible augmentation. These patients were then assessed by expert panel using the MPI criteria | Clinically significant augmentation: 2.7% (5/185 patients) |
Miranda 2013 [30] | Switching study | 18 months | 10 | None described | None reported |
Ropinirole | |||||
Montplaisir 2006 [31] | Single-blind phase followed by double-blind treatment | SB: 24 weeks DB: 12 weeks | 202 | Augmentation recorded as an adverse event (AE) | Possible augmentation Ropinirole: 1.5% (3/202 patients) |
Garcia-Borreguero 2007 [9] | Open-label, continuation of double-blind, randomized, placebo-controlled trial | 52 weeks | 310 | Retrospective assessment of AEs | 9.1% (28/309) had AEs coded to RLS 2.3% (7/30) had AEs recorded as augmentationb |
Garcia-Borreguero 2012 [32] | Double-blind, randomized, placebo-controlled trial followed by open-label continuation | DB: 26 weeks OL: 40 weeks | DB: 404 OL: 269 | ASRS Potential cases prospectively identified by a structured diagnostic interview and by reporting of AEs, and then evaluated by an expert panel based on the NIH criteria | Clinically significant augmentation DB: 3% (5/197) patients on rotigotine; 0.48% (1/207) patients on placebo OL: 2% (5/269 patients)c |
Pramipexole | |||||
Montplaisir 2000 [33] | Open-label continuation of double-blind study | Mean: 7.8 months | 7 | Not specified | None reported |
Ferini-Strambi 2002 [16] | Open-label trial | ≥6 months | 60 | Not specified | 8.3% (5/60 patients) |
Silber 2003 [34] | Retrospective chart review | 30 months | 60 | New development or increase in severity, duration, or anatomic distribution of RLS/WED earlier in the day than the time a medication for RLS/WED was taken | 33% (16/49 patients) |
Winkelman 2004 [15] | Retrospective chart review | Average of 21.2 ± 11.4 months; range: 6–60 months | 59 | Earlier RLS/WED symptom appearance (≥5 times/week) requiring earlier administration of medications (>2 h) Extension of symptoms beyond legs | 32% (19/59) of patients |
Trenkwalder 2006 [35] | Double-blind, randomized, placebo-controlled withdrawal study | 3 months (following 6 months OL treatment) | Pramipexole: 78 Placebo: 72 | ASRS | None reported |
Inoue 2010 [36] | Open-label, continuation of double-blind, randomized, placebo-controlled trial | 52 weeks | 141 (Japanese pts) | Patient diary Defined as symptom appearance ≥ 2 h earlier than usual for ≥ 5 days/week
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