A comprehensive update on the ADMET considerations for α2δ calcium channel ligand medications for treating restless legs syndrome

ABSTRACT

Introduction

Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is a sleep-related sensory-motor disorder associated with poor sleep quality and impaired daily functioning. In patients affected by chronic RLS/WED, a pharmacological therapy is recommended. International guidelines suggest to start the treatment with a α2δ calcium channel ligand in most cases, unless contraindicated.

Areas covered

The present review is based on an extensive Internet and PubMed search from 1986 to 2024. Our purpose is to describe the absorption, distribution, metabolism, and toxicology (ADMET) of the α2δ ligands, with common consideration for the therapeutic class, specificities of different compounds, efficacy, and safety in relation to other treatment options.

Expert opinion

α2δ ligands are quite similar in their ADMET profiles, sharing most of the pharmacokinetics and potential adverse effects. However, we highlight the linear kinetic of gabapentin enacarbil and pregabalin, differently from gabapentin. α2δ ligands are safe and effective for the treatment of RLS/WED. Additional benefits can be obtained in comorbid insomnia, chronic pain syndromes, history of impulse control disorder, and comorbid anxiety. The use of α2δ ligands is associated with poor risk of augmentation. We still need new long-term safe and effective treatments, which could be developed along with our knowledge of RLS/WED pathophysiology.

KEYWORDS:

• Restless legs syndrome
• Willis-Ekbom disease
• α2δ calcium channel ligands
• pregabalin
• gabapentin
• gabapentin enacarbil
• ADMET
• dopamine agonists

Article highlights

• Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is a sleep-related sensorimotor disorder defined by an urgency to move the legs, usually combined with unpleasant sensations, which occurs or worsens during rest, and disappears with movement of the legs. Significant distress in sleep and life quality is associated with RLS/WED.

• Updated international guidelines recommend α2δ calcium channel ligands as the first-line treatment of chronic RLS/WED, unless contraindicated due to specific medical or psychiatric conditions.

• α2δ ligands are quite similar in their ADMET profiles, sharing most of the pharmacokinetics and potential adverse effects. Between distinctive features, we highlight the linear kinetic of gabapentin enacarbil and pregabalin, differently from gabapentin; in addition, only the latter can be used during breastfeeding in selected cases.

• The use of α2δ ligands is associated with poor risk of augmentation, in contrast to dopamine agonists. Rotigotine is related to a lower rate of augmentation, compared to other dopaminergic agents. A first-line treatment with a dopaminergic drug may reduce the future response to a second-line therapy with an α2δ ligand.

• Additional benefits in comorbid insomnia, chronic pain, and anxiety may be obtained when starting the treatment with an α2δ ligand. It can also be used in polytherapy, in order to keep low dosages of other drugs and reducing possible adverse events.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.