Use of α2δ Ligands for Restless Legs Syndrome/Willis Ekbom Disease

Faulkner, Michele A.

doi:10.1007/s40263-018-0502-z

Cited by 15 publications

(10 citation statements)

References 97 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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 ).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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The Safety and Efficacy of Pregabalin Add-on Therapy in Restless Legs Syndrome Patients

et al. 2021

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Pregabalin is increasingly being used as a first-line treatment for symptomatic control of restless legs syndrome (RLS). This study aimed to evaluate the efficacy and safety of pregabalin as add-on therapy in RLS patients already taking dopamine agonists (DA) but still in need of further management. Patients with idiopathic RLS were enrolled, and all had already been prescribed DA for at least 3 months but still had either persistent symptoms, side effects, or comorbid insomnia. An initial dose of 75 mg pregabalin was begun, adjusted as needed, and maintained at a stable dose for 4 weeks, followed by observation for a total of 8 weeks. RLS symptoms and insomnia scores were evaluated before and after add-on pregabalin treatment. Patients were monitored for side effects that could be attributed to pregabalin. A total of 32 RLS patients were enrolled, and 20 subjects remained until the endpoint. After the pregabalin add-on, the mean IRLS score showed significant improvement compared to the baseline (p < 0.001). The insomnia severity index score also improved (p = 0.036), and no serious adverse effects were observed. Our preliminary data suggests the potential for pregabalin as an add-on therapy to DA with regards to both efficacy and safety in patients who have inadequate RLS improvement.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Safety and Efficacy of Pregabalin Add-on Therapy in Restless Legs Syndrome Patients

et al. 2021

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“…Studies also conclude that the use of dopamine or α-2-δ calcium-channel ligand is recommended as the first-line treatment for RLS along with other agents depending on other factors including, the severity of RLS, cognitive function, and comorbid conditions [43]. In 2018, Faulkner reported that α-2-δ ligands were a better choice for RLS compared to dopamine agonists as α-2-δ ligands were both safer and more effective compared to dopamine agonists [44].…”

Section: Therapeutic Approaches To Rlsmentioning

confidence: 99%

Unraveling the Mysteries of Restless Leg Syndrome

Memon

Zaveri

Perry

et al. 2020

Cureus

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Restless leg syndrome (RLS) or Willis-Ekbom disease (WED) is an under-diagnosed, chronic, and progressive primary sensory-motor disorder. It is characterized by an uncontrollable urge to move the legs due to uncomfortable and sometimes painful sensations, with a diurnal variation. RLS can lead to severe sleep disturbances, a usual cause of consultation. The pathophysiology is known partially, and it is believed that there is an association between the different variants of genetic mutations combined with dopaminergic and brain iron dysregulation, which plays an important role. The data used for this study were extracted from the articles found in the PubMed database that discuss different gene variants, pathophysiology, and various methods of treatment. They also highlight the role of iron in the pathogenesis of RLS as it is required for the synthesis of tyrosine hydroxylase, which is the rate-limiting step for dopamine synthesis. This review article provides a clinically useful overview of RLS in terms of pathophysiological findings, its genetic associations, and therapeutic options by using the currently available literature. Because RLS presents with vague symptoms and shares similarities with many other diseases, it might be overlooked by many physicians resulting in underdiagnosis and under-treatment. While these discoveries provide a breakthrough in understanding the details of RLS, further studies are recommended as these studies are limited to animal models and provide a limited representation of the general population.

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“…As a result, gabapentinoids are useful drugs in the treatment of several neuropathies, such as neuropathic pain 2 and fibromyalgia 3 and other nonpain indications, such as epilepsy 4 or restless leg syndrome. 5 The overall function of the α2δ subunit is still a matter of intense research. 6 The mechanism of calcium current increase is unknown, and it can only be partially explained by an increase in the trafficking of the channels to augment their amount on the cell surface.…”

mentioning

confidence: 99%

Piperazinyl Bicyclic Derivatives as Selective Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels

Fernández¹,

Dı́az²,

Garcia³

et al. 2021

ACS Med. Chem. Lett.

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The synthesis and pharmacological activities of a new series of piperazinyl quinazolin-4-(3H)-one derivatives acting toward the α2δ-1 subunit of voltage-gated calcium channels (Ca v α2δ-1) are reported. Different positions of a micromolar HTS hit were explored, and best activities were obtained for compounds containing a small alkyl group in position 3 of the quinazolin-4-(3H)-one scaffold and a 3-methyl-piperazin-1-yl-or 3,5-dimethylpiperazin-1-yl-butyl group in position 2. The activity was shown to reside in the R enantiomer of the chain in position 2, and several eutomers reached single digit nanomolar affinities. Final modification of the central scaffold to reduce lipophilicity provided the pyrido [4,3-d]pyrimidin-4(3H)-one 16RR, which showed high selectivity for Ca v α2δ-1 versus Ca v α2δ-2, probably linked to its improved analgesic efficacy-safety ratio in mice over pregabalin.

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Use of α2δ Ligands for Restless Legs Syndrome/Willis Ekbom Disease

Cited by 15 publications

References 97 publications

The Safety and Efficacy of Pregabalin Add-on Therapy in Restless Legs Syndrome Patients

The Safety and Efficacy of Pregabalin Add-on Therapy in Restless Legs Syndrome Patients

Unraveling the Mysteries of Restless Leg Syndrome

Piperazinyl Bicyclic Derivatives as Selective Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels

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