Restless legs syndrome is a sensorimotor neurological disorder with a worldwide prevalence of 5–10%, and 2–3% of patients having symptoms severe enough to seek treatment (1). The discomfort and urge to move the legs, which is the prominent symptom of restless legs syndrome (RLS), occurs mainly at night. Symptomatic patients suffer from sleep disturbance and their quality of life deteriorates as a consequence (2).

Dopamine agonists (DA) are known to relieve RLS symptoms (3) and are commonly used as first-line treatment (4). Acute treatment with DA can result in side effects that may limit dose escalation and thus limit the ability of DA to fully treat the symptoms. Adverse events were documented for 79% during the first trial year of rotigotine (5), and 19–24% discontinued pramipexole by 1 year (6). Previous studies have demonstrated that despite improving symptoms, DA does not always improve sleep quality (7) and it may cause insomnia in some patients. Finally, some patients may only have partial benefits even at the acceptable, upper-dose limits. Treatment options for physicians who have to deal with these problems when trying to treat patients include moving to an alternative class of agents or add-on a second medication from an alternative class of agents. One of these alternative agents is pregabalin (6).

Pregabalin has been shown to be an effective monotherapy for managing RLS symptoms when compared to placebo or active treatment with a DA (6, 8–10). However, there have been no studies using pregabalin as an add-on agent with DA. Studies with pregabalin in RLS have reported that pregabalin is effective in improving not only RLS symptoms but also sleep structure (6, 9). Other drugs are considered second-line treatment options and have several side effects. Benzodiazepines have dependency, falling, and reduction of deep sleep issues. Opioids have many side effects such as sedation, constipation, mood change, opioid-induced respiratory depression, and dependence (11). Therefore, pregabalin shows promise as a non-dopaminergic “add-on” treatment option that might complement and compensate for some limitations with the use of single-agent DA (4, 12). The purpose of this study was to evaluate the efficacy and safety of pregabalin as add-on therapy in patients who were on DA for RLS but for whom further symptomatic improvement was needed.

A total of 32 participants were enrolled at the first visit: six had side effects limiting increases in DA, 10 had co-morbid insomnia, and 16 had persistence of symptoms. Among the 32 participants, 12 had dropped out by Week 8. The causes of the dropouts were as follows: three were related to drug adverse effects (dizziness or sedation), two were unwilling to travel the long distance required, three were related to drug ineffectiveness, and four had personal reasons for not returning to the clinic, but unrelated to drug issues. In this group, the dose of pramipexole (N = 8) ranged from 0.125 to 0.75 mg and ropinirole (N = 4) from 0.25 to 2 mg. The median (range) treatment duration with DA was 727.08 ± 867.21 days (91–2,529 days). Additionally, 20 participants completed the Week 8 endpoint (Figure 1). The dose of pramipexole (N = 18) ranged from 0.125 to 0.5 mg, and ropinirole (N = 2) from 0.75 to 2 mg. The median (range) treatment duration with DA of the 20 participants was 472.65 ± 427.45 days (92–2,376 days). At Week 8 endpoint, 19 patients were on pregabalin 75 mg and one was on pregabalin 150 mg.

Regarding further results, 81 percent were women, mean age 59 ± 13 years. RLS duration was 12 ± 10 years with IRLS 25.7 ± 7.2, and RLS VAS 51.9 ± 32.9 when they enrolled. Moreover, 7 (21.9%) patients had clinical insomnia with ISI over 15, 15 (46.9%) were poor sleepers with PSQI over 8.5, 2 (6.3%) showed anxiety, while 10 (31.3%) had depressed moods. Hemoglobin and ferritin were within the normal range.

After adding pregabalin, RLS severity was significantly improved with mean IRLS lowered from 26.5 to 20.9 (p < 0.001) and the ISI showed statistically significant improvement (Table 1). None of the other scales were significantly different from the baseline. A total of six patients reported the following adverse effects on pregabalin: dizziness in two patients; sleepiness in two patients, drooling in one patient, and mild rash in one patient. Among the six patients who reported side effects, three completed the Week 8 visit.

This study showed the usefulness of pregabalin as an add-on treatment in patients who continue to have problems with RLS, despite DA use, over 8 weeks. From the perspective of RLS severity, adding pregabalin resulted in a statistically significant improvement, manifested by an improved IRLS score.

Pregabalin binds to voltage-gated calcium channels, inhibits calcium entry, and results in lowering glutamate activity and therefore decreasing excitation (20). This mechanism is hypothesized to exert an effect on RLS treatment (12). Pregabalin has several additional beneficial aspects in the management of RLS that should also be considered. Firstly, pregabalin has a positive effect on sleep (21). Current guidelines for RLS management also suggest that if patients have comorbid insomnia or sleep disturbance disproportionate to other symptoms of RLS, alpha-2-delta ligands could be first-line treatment (4). In our study, ISI was improved, indicating that pregabalin could be helpful as an add-on therapy for RLS patients with insomnia. Secondly, pregabalin is capable of controlling other comorbidities in RLS patients. As one of the alpha-2-delta ligands, it can be effective in controlling neuropathic pains and anxiety, for example (12). In addition, interaction with the BK channel has been suggested to reduce neuropathic pains (22). As regards its safety, pregabalin was well-tolerated, in line with previous studies that reported pregabalin is generally well-tolerated (9).

Generally, pregabalin is prescribed at doses ranging from 50 to 450 mg (4) and previous randomized controlled trials showed an effect in doses of over 150 mg as monotherapy (6, 9, 10). In our study, the dose of 75 mg was maintained in the majority of patients as add-on treatment. This relatively low dosage may be related to the fact that pregabalin was used as add-on therapy, not as monotherapy where dosages are routinely higher.

This study has several limitations. Our sample size was small, and the drop-out rate was moderate. The study was an unblinded, open-label study for which placebo effects could contribute to the effects we measured. Measures of sleep quality and periodic legs movement quantification during sleep on overnight polysomnography would have provided more “objective” treatment measurements.

In patients who continued to have problems with RLS symptoms despite being on a DA, pregabalin might be considered as add-on therapy to further improve RLS symptoms, thereby reducing some of the covariant insomnia problems associated with DA usage. The data supported the value of a future randomized, double-blind, placebo-controlled clinical trial in a larger population of RLS patients for whom DA are primary treatments but are not fully effective.

The original contributions presented in the study are included in the article/supplementary files, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Keimyung University Dongsan Medical Center. The patients/participants provided their written informed consent to participate in this study.

YC and CE conceptualized research. HB and YC made contributions to the investigation. KK, YC, and CE analyzed data. HB wrote the original draft. YC, CE, and RA supervised. All authors have reviewed and edited and contributed to data curation and methodology.

This study was supported by funding from Pharmascience Korea, Inc. Pharmascience Korea was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.

This study received funding from Pharmascience Korea, Inc. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. All authors declare no other competing interests.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.