How to Reduce Augmentation Risk in Restless Legs Syndrome

Stefan Clemens, PhD, from the department of physiology at Brody School of Medicine at East Carolina University, was awarded a patent in 2020 for his novel method for treating RLS, and the drug candidate is currently being developed.

Dopaminergic medications target the dopamine-3 receptor, which has a calming effect on the nervous system. However, research conducted by Clemens’ laboratory using animal models showed that long-term use of these treatments can result in increased levels of the dopamine-1 receptor, which has an excitatory effect and may be the cause of augmentation.⁶ 

Clemens proposed a new treatment approach that targets the increased dopamine-1 receptor levels in RLS patients who experience augmentation, thereby reducing activation of dopamine-1 receptors while still providing symptom relief. “Lofty goal, but it could get rid of the augmentation,” says Clemens. 

East Carolina University issued Emalex Biosciences Inc patent rights of ecopipam (EBS-101) in March 2022, the investigational, first-in-class dopamine-1 receptor antagonist to advance clinical studies for the treatment of RLS with augmentation. The drug candidate is now approaching phase 2 clinical trials. 

While EBS-101 shows promise, any long-term side effects remain to be seen, Clemens says. “To some extent, it’s really, really cool, but then pramipexole had also a huge effect as soon as it was being prescribed,” he says.

References

1. Augmentation: diagnosis and treatment. Restless Legs Syndrome Foundation brochure. Available at https://www.rls.org/file/member-publications/handouts/RLS-AUGMENTATION-5-3-22.pdf
2. Silber MH, Buchfuhrer MJ, Earley CJ, et al. The management of restless legs syndrome: an updated algorithm. Mayo Clinic Proceedings. 2021 July;96(7):1921-37.
3. Management of restless legs syndrome and periodic limb movement disorder in adults. UpToDate website. Available at https://www.uptodate.com/contents/management-of-restless-legs-syndrome-and-periodic-limb-movement-disorder-in-adults?csi=6e770f7e-ca27-446d-b542-eb260cc8d0ac&source=contentShare
4. Allen RP, Picchietti DL, Auerbach M, et al. Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report. Sleep Med. 2018 Jan;41:27-44.
5. Vetrugno R, La Morgia C, D’Angelo R, et al. Augmentation of restless legs syndrome with long-term tramadol treatment. Mov Disord. 2007 Feb 15;22(3):424-27.
6. Clemens S, Ghorayeb I. D3 and D1 receptors: The Yin and Yang in the treatment of restless legs syndrome with dopaminergics. Adv Pharmacol. 2019 Feb 18;84:79-100.

Photo caption: Known for his restless legs syndrome expertise, William Ondo, MD, cares for many patients who are already experiencing augmentation when they first enter his practice.

Photo credit: Humberto Jamie/Houston Methodist