A Narrative Review of the Lesser Known Medications for Treatment of Restless Legs Syndrome and Pathogenetic Implications for Their Use

Yeh, Paul; Spruyt, Karen; DelRosso, Lourdes M.; Walters, Arthur S.

doi:10.5334/tohm.739

Cited by 4 publications

(3 citation statements)

References 85 publications

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“… 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. Hyperglutamatergicity in the thalamus has also been demonstrated in RLS compared to controls through proton magnetic spectroscopy ( 1 H MRS) neuroimaging studies ( P = 0.016).…”

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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“…Other off-label drugs, including cannabis products, may have potential for symptom relief, but preliminary observations suggest that efficacy may be variable and that sedation and other side effects can be problematic for some people. 19 …”

Section: Discussionmentioning

confidence: 99%

Aripiprazole, a Novel Option in the Management of Restless Legs Syndrome (RLS) Patients with Augmentation and/or Severe RLS Symptoms: A Report of 4 Cases

Lee,

Spitale,

Robillard

2023

NSS

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Purpose Restless Legs Syndrome (RLS) is a sensorimotor disorder associated with an unpleasant urge to move the limbs, relieved with movement, occurring in the evenings and with prolonged rest/inactivity. Treatment with dopamine agonists is effective for up to 60–90% of affected individuals. However, augmentation, ie, the paradoxical worsening of RLS symptoms after prolonged RLS treatment, is frequently reported, typically after 3–10 years of treatment. Here, we present 4 patients with RLS who were successfully treated with dopamine agonists but later developed augmentation. A trial of aripiprazole, a dopamine receptor partial agonist (DRPA), was initiated for treatment of augmentation symptoms. Patients and Methods Four patients treated for RLS with dopamine agonists developed augmentation. In each instance, augmentation symptoms did not respond adequately to a variety of medications including α2δ drugs, opioids or other agents. A trial of aripiprazole was initiated for each patient, and effects were evaluated. Results All four patients with severe RLS and augmentation with dopamine agonists achieved symptom control with aripiprazole. Patients endorsed 90–100% efficacy with aripiprazole by subjective self-report after failures with other agents. Further evaluation with the International Restless Legs Syndrome Study Group RLS Rating Scale (IRLS-SGRS) showed that benefits (from moderate to very severe, to mild to moderate severity) were largely maintained for 1–2 years. Aripiprazole doses to control augmentation symptoms were low (1–4 mg). No significant side effects were reported. Conclusion Aripiprazole may have utility for augmentation in RLS. We speculate that the partial agonist and antagonist properties of aripiprazole may limit potential for dopamine hyposensitization to progress to cause augmentation. Further research is needed to see if aripiprazole and/or other DRPAs are a viable long-term treatment option for patients experiencing augmentation and/or severe RLS with dopamine agonist therapy.

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“…The current overview summarizes the literature on the use of benzodiazepines for the treatment of RLS as well as the use of benzodiazepines for the treatment of Periodic Limb Movements of Sleep (PLMS) which are a frequent accompaniment of RLS. As clonazepam is so commonly used in RLS, we did not include it in our previous review of the lesser-known treatments for RLS [3].…”

Section: Introductionmentioning

confidence: 99%

A Historical Overview of the Role of Benzodiazepines including Clonazepam in the Treatment of Adult Restless Legs Syndrome and Periodic Limb Movements in Sleep

Walters,

Spruyt,

et al. 2024

Tremor and Other Hyperkinetic Movements

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In a recent survey of 16,694 people receiving treatment for Restless Legs Syndrome (RLS), approximately 25% were treated with benzodiazepines either singly or in combination with other RLS treatments. Because of the large number of people receiving benzodiazepines for treatment of RLS, we conducted a historical overview of the therapeutic role of benzodiazepines in RLS and its associated condition Periodic Limb Movements in Sleep (PLMS). We found 17 articles on the use of clonazepam in RLS, PLMS, or both, 3 on triazolam and PLMS, 1 on alprazolam and RLS, 1 on temazepam and PLMS, and 1 on nitrazepam and PLMS. The order of benefit of benzodiazepines from the summarized literature is Sleep>RLS>PLMS and arousals > PLMS. Most of the studies on clonazepam employed dosages of 0.5-2.0 mg. Dosages of 3 or 4 mg caused lethargy, somnolence and confusion. An epidemiological study on the therapy of RLS suggests that treatment of RLS with most types of RLS medications including benzodiazepines in combination with other RLS therapies lowers the future cardiovascular risk associated with RLS. The major effect of benzodiazepines is through potentiation of the effect of GABA on the GABA A receptor. Neuroimaging studies suggest that GABA is altered either positively or negatively in various brain regions in RLS and genetic studies suggest that there are alterations in the GABA receptor in RLS. These results suggest that medications with different GABAergic mechanisms such as tiagabine (Gabitril) or others should be investigated in RLS for their possible therapeutic benefit. HIGHLIGHTSBenzodiazepines are frequently used as therapy in Restless Legs Syndrome (RLS) and Periodic Limb Movements in Sleep. The order of benefit is Sleep>RLS>PLMS and arousals > PLMS. For clonazepam dosages of 0.5 mg-2.0 mg/day are most frequently employed. Benzodiazepines exert their therapeutic effect through GABA-ergic mechanisms.

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A Narrative Review of the Lesser Known Medications for Treatment of Restless Legs Syndrome and Pathogenetic Implications for Their Use

Cited by 4 publications

References 85 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

Aripiprazole, a Novel Option in the Management of Restless Legs Syndrome (RLS) Patients with Augmentation and/or Severe RLS Symptoms: A Report of 4 Cases

A Historical Overview of the Role of Benzodiazepines including Clonazepam in the Treatment of Adult Restless Legs Syndrome and Periodic Limb Movements in Sleep

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