Effect of Gabapentin Enacarbil on Individual Items of the International Restless Legs Study Group Rating Scale and Post-sleep Questionnaire in Adults with Moderate-to-Severe Primary Restless Legs Syndrome: Pooled Analysis of 3 Randomized Trials

Ahmed, Mansoor M.; Hays, Ryan; Poceta, J. Steven; Jaros, Mark; Kim, Richard; Shang, Gwendoline

doi:10.1016/j.clinthera.2016.05.008

Cited by 9 publications

(2 citation statements)

References 35 publications

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“… 76–79 In double-blind clinical studies, for example, medications such as gabapentin and pregabalin, which are moderately effective in improving sleep and PLMS in RLS, work by interacting with the alpha-2 delta-subunit of the voltage-gated calcium channel to prevent the release of glutamate from glutamatergic terminals. 76–78 , 80 Other medications for which there are less rigorous clinical studies, but which claim some benefit in RLS, include the NMDA glutamate receptor antagonists, amantadine and ketamine and the AMPA glutamate receptor antagonist, perampanel. 81 Interestingly, methadone, in addition to its opioid agonist properties, also has NMDA receptor blocking properties.…”

Section: Future Researchmentioning

confidence: 99%

Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome

Walters,

Li,

Koo

et al. 2023

Brain

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Restless legs syndrome (RLS) is responsive to opioid, dopaminergic, and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, β-endorphin, and perhaps metenkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta, and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS, and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anemia, and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic Hormone (ACTH) and α-Melanocyte Stimulating Hormone (α-MSH) are derived from Pro-opiomelanocortin (POMC) as is β-endorphin. However, they cause RLS-like symptoms and Periodic Limb Movements (PLMS) when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.

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Section: Future Researchmentioning

confidence: 99%

Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome

Walters,

Li,

Koo

et al. 2023

Brain

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“…Similarly, in our NMA, we found gabapentin effective in treatment of RLS, it has also been proven more effective in improving sleep and awakening quality compared with ropinirole (Saletu et al, 2010 ). Many randomized controlled trials have demonstrated the efficacy of gabapentin enacarbil in the treatment of RLS, it can significantly improve sleep quality, mood disturbances and quality of life vs. placebo in RLS (Ahmed et al, 2016 ; Avidan et al, 2016 ). Gabapentin enacarbil was designed to provide sustained gabapentin exposure and a delayed peak plasma concentration compared with an equivalent dose of gabapentin, resulting in overcome the pharmacokinetic deficiencies of gabapentin (Cundy et al, 2004 , 2008 ).…”

Section: Discussionmentioning

confidence: 99%

The Efficacy and Safety of Pharmacological Treatments for Restless Legs Syndrome: Systemic Review and Network Meta-Analysis

Zhou

Liang

et al. 2021

Front. Neurosci.

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Although various drugs are currently used for restless legs syndrome (RLS) in clinic, selecting appropriate drugs for patients is difficult. This network meta-analysis (NMA) aimed to compare the efficacy and safety of different drugs. After literature searching and screening, 46 trials, including 10,674 participants are included in this NMA. The pooled results showed that, compared with placebo, only levodopa is inefficient to relieve symptoms of RLS. Cabergoline decreases IRLS scores to the greatest extent among all drugs (MD −11.98, 95% CI −16.19 to −7.78). Additionally, pramipexole is superior to ropinirole in alleviating symptoms of RLS (MD −2.52, 95% CI −4.69 to −0.35). Moreover, iron supplement alleviates RLS symptoms significantly compared with placebo in patient with iron deficiency (MD −5.15, 95% CI −8.99 to −1.31), but not for RLS patients with normal serum ferritin level (MD −2.22, 95% CI −6.99 to 2.56). For primary RLS, these drugs are also effective, while there is insufficient data to analyze drug efficacy in secondary RLS. We analyzed risk of common adverse effects of drugs including nausea, somnolence, fatigue, headache and nasopharyngitis. Alpha-2-delta ligands and DAs are favorable choices for both primary and secondary RLS because of their significant efficacy and good tolerability. Iron supplement can significantly alleviate symptoms of RLS patients with iron deficiency than placebo. We recommend gabapentin, gabapentin enacarbil, and pregabalin for clinicians for first consideration mainly because that they rarely cause augmentation. Oxycodone-naloxone could be considered in patients with severe or very severe RLS who failed in treatment with above drugs.

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Update on Restless Legs Syndrome: from Mechanisms to Treatment

Gonzàlez‐Latapi¹,

Malkani

2019

Curr Neurol Neurosci Rep

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Effect of Gabapentin Enacarbil on Individual Items of the International Restless Legs Study Group Rating Scale and Post-sleep Questionnaire in Adults with Moderate-to-Severe Primary Restless Legs Syndrome: Pooled Analysis of 3 Randomized Trials

Cited by 9 publications

References 35 publications

Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome

Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome

The Efficacy and Safety of Pharmacological Treatments for Restless Legs Syndrome: Systemic Review and Network Meta-Analysis

Update on Restless Legs Syndrome: from Mechanisms to Treatment

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