List of investigational restless legs syndrome drugs

This is a dynamic list and may never be able to satisfy particular standards for completeness. You can help by editing the page to add missing items, with references to reliable sources.

This is a list of investigational restless legs syndrome drugs, or drugs that are currently under development for clinical use for the treatment of restless legs syndrome (RLS) but are not yet approved.

Chemical/generic names are listed first, with developmental code names, synonyms, and brand names in parentheses. The format of list items is "Name (Synonyms) – Mechanism of Action [Reference]".

This list was last comprehensively updated in September 2025. It is likely to become outdated with time.

Under development

Phase 3

• Ferric carboxymaltose (Ferinject; Injectafer; Iron-dextri-maltose; Iroprem; Renegy; VIT-45; Z-213) – iron replacement

Phase 2

• BP-14979 (BP-1.4979) – dopamine D₃ receptor partial agonist
• Ropinirole transdermal (Haruropi Tape; HP-3000) – dopamine D₂-like receptor agonist

Preclinical

• ATH-399A (DWP-307399; HL-192) – nuclear receptor subfamily 4 group A member 2 (NR4A2) agonist

Not under development

Suspended

• Aplindore (DAB-452; Palindore; SLS-006; WAY-DAB-452) – dopamine D₂-like receptor agonist

No development reported

• NLS-2 (NLS2) – iron replacement
• Research programme: cannabinoid-based therapeutics - Axim Biotechnologies (Cannabidiol/Gabapentin; Cannbleph) – various actions

Discontinued

• Entacapone (Comtan; Comtess; OR-611) – catechol O-methyltransferase (COMT) inhibitor
• IPX-159 – undefined mechanism of action
• Istradefylline (KW-6002; Nourianz; Nouriast) – adenosine A_2A receptor antagonist
• Pregabalin (CI-1008; isobutylgaba; Lyrica; PD-144723) – gabapentinoid (α₂δ subunit-containing voltage-gated calcium channel ligand)
• Radafaxine (GW-353162; (2S,3S)-hydroxybupropion) – norepinephrine–dopamine reuptake inhibitor (NDRI)
• Research programme: dopamine receptor agonists - DarPharma (DAR-0300) – dopamine receptor agonist
• Safinamide (EMD-1195686; Equfina; FCE-26743; ME-2125; NW-1015; Onstryv; PNU-151774; Xadago; ZP-034) – monoamine oxidase MAO-B inhibitor and other actions

Clinically used drugs

Approved drugs

• Gabapentin enacarbil (ASP-8825; GSK-1838262; Horizant; Regnite; Solzira; XP-13512) – gabapentinoid (α₂δ subunit-containing voltage-gated calcium channel ligand)
• Oxycodone/naloxone (naloxone/oxycodone; Targin; Targinact; Targiniq) – combination of oxycodone (μ-opioid receptor agonist) and naloxone (orally inactive opioid receptor antagonist) (only in severe and treatment-refractory cases) [1] ^{[2] [3]}
• Pramipexole (BI-Sifrol; Daquiran; Mirapex; Mirapexin; Pexola; Sifrol; SND-919) – dopamine D₂-like receptor agonist
• Ropinirole (Adartrel; Repreve; Requip; Ropinirole IR) – dopamine D₂-like receptor agonist
• Rotigotine transdermal (Leganto; N-0437; N-0923; Neupro; Nubrenza; SPM-962) – dopamine D₂-like receptor agonist

Off-label drugs

• Benzodiazepines (GABA_A receptor positive allosteric modulators) (e.g., clonazepam) ^{[4] [5] [6]}
• Dopamine precursors (indirect dopamine receptor agonists) (e.g., carbidopa/levodopa) ^{[4] [5]}
• Dopamine D₂-like receptor agonists (e.g., cabergoline, pergolide) ^{[5] [4]}
• Gabapentinoids (α₂δ subunit-containing voltage-gated calcium channel ligands) (e.g., gabapentin, pregabalin) ^{[5] [4]}
• Iron supplements (e.g., ferrous sulfate) ^{[5] [4] [7] [8]}
• Opioids (μ-opioid receptor agonists) (e.g., tramadol, codeine, morphine, oxycodone, hydrocodone, methadone, buprenorphine) (only in severe and treatment-refractory cases) ^{[5] [4] [9]}
• Others (e.g., amantadine, baclofen, bupropion, cannabis/cannabinoids, carbamazepine, clonidine, corticosteroids, dipyridamole, ketamine, lamotrigine, levetiracetam, orphenadrine, oxcarbazepine, perampanel, physostigmine, rasagiline, rifaximin, selegiline, topiramate, valproic acid) ^{[5] [4] [10] [11] [12] [13] [14]}

See also

• List of investigational drugs
• List of investigational Parkinson's disease drugs

References

1. de Biase S, Valente M, Gigli GL (2016). "Intractable restless legs syndrome: role of prolonged-release oxycodone-naloxone". Neuropsychiatr Dis Treat. 12: 417–425. doi: 10.2147/NDT.S81186 . PMC   4770072 . PMID   26966363.
2. Frampton JE (June 2015). "Oxycodone/Naloxone PR: A Review in Severe Refractory Restless Legs Syndrome". CNS Drugs. 29 (6): 511–518. doi:10.1007/s40263-015-0254-y. PMID   26135898.
3. Gemignani, Franco; Parrino, Liborio; Melpignano, Andrea; Milioli, Giulia; Riccardi, Silvia (2016). "Restless legs syndrome: a new entity of neuropathic pain? Treatment with prolonged release oxycodone/naloxone combination". Journal of Parkinsonism and Restless Legs Syndrome: 23. doi: 10.2147/JPRLS.S77560 . ISSN   1927-7733.
4. Silber MH, Buchfuhrer MJ, Earley CJ, Koo BB, Manconi M, Winkelman JW (July 2021). "The Management of Restless Legs Syndrome: An Updated Algorithm". Mayo Clin Proc. 96 (7): 1921–1937. doi: 10.1016/j.mayocp.2020.12.026 . PMID   34218864.
5. Winkelman JW, Berkowski JA, DelRosso LM, Koo BB, Scharf MT, Sharon D, Zak RS, Kazmi U, Carandang G, Falck-Ytter Y, Shelgikar AV, Trotti LM, Walters AS (January 2025). "Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment". J Clin Sleep Med. 21 (1): 153–199. doi:10.5664/jcsm.11392. PMC   11701280 . PMID   39324664.
6. Walters AS, Spruyt K, Ba DM, Gao X (2024). "A Historical Overview of the Role of Benzodiazepines including Clonazepam in the Treatment of Adult Restless Legs Syndrome and Periodic Limb Movements in Sleep". Tremor Other Hyperkinet Mov (N Y). 14 21. doi: 10.5334/tohm.824 . PMC   11067967 . PMID   38708125.
7. Earley CJ, Jones BC, Ferré S (October 2022). "Brain-iron deficiency models of restless legs syndrome". Exp Neurol. 356 114158. doi:10.1016/j.expneurol.2022.114158. PMC   9357217 . PMID   35779614.
8. Avni T, Reich S, Lev N, Gafter-Gvili A (May 2019). "Iron supplementation for restless legs syndrome - A systematic review and meta-analysis". Eur J Intern Med. 63: 34–41. doi:10.1016/j.ejim.2019.02.009. PMID   30798983.
9. Silber MH, Becker PM, Buchfuhrer MJ, Earley CJ, Ondo WG, Walters AS, Winkelman JW (January 2018). "The Appropriate Use of Opioids in the Treatment of Refractory Restless Legs Syndrome". Mayo Clin Proc. 93 (1): 59–67. doi:10.1016/j.mayocp.2017.11.007. PMID   29304922.
10. Yeh PG, Spruyt K, DelRosso LM, Walters AS (2023). "A Narrative Review of the Lesser Known Medications for Treatment of Restless Legs Syndrome and Pathogenetic Implications for Their Use". Tremor Other Hyperkinet Mov (N Y). 13 7. doi: 10.5334/tohm.739 . PMC   9983500 . PMID   36873914.
11. Burini A, Pellitteri G, Merlino G, Nilo A, Tereshko Y, Dolso P, Gigli GL, Valente M (October 2024). "Current and emerging pharmaceutical strategies for the treatment and management of restless legs syndrome". Expert Rev Neurother. 24 (10): 997–1009. doi:10.1080/14737175.2024.2385947. PMID   39082506.
12. Riccardi S, Ferri R, Garbazza C, Miano S, Manconi M (April 2023). "Pharmacological responsiveness of periodic limb movements in patients with restless legs syndrome: a systematic review and meta-analysis". J Clin Sleep Med. 19 (4): 811–822. doi:10.5664/jcsm.10440. PMC   10071388 . PMID   36692194.
13. Bayard M, Bailey B, Acharya D, Ambreen F, Duggal S, Kaur T, Rahman ZU, Roller K, Tudiver F (2011). "Bupropion and restless legs syndrome: a randomized controlled trial". J Am Board Fam Med. 24 (4): 422–428. doi:10.3122/jabfm.2011.04.100173. PMID   21737767.
14. Ghorayeb I (2021). "Cannabis for Restless Legs Syndrome". Cannabinoids and Sleep. Adv Exp Med Biol. Vol. 1297. pp. 173–181. doi:10.1007/978-3-030-61663-2_13. ISBN   978-3-030-61662-5. PMID   33537945.

External links

• AdisInsight - Springer