What is the role of ketamine in the treatment of restless legs syndrome (RLS) in patients who have not responded to first-line treatments, such as dopamine agonists or opioids?

Ketamine in the Treatment of Restless Legs Syndrome

Ketamine is not recommended for the treatment of restless legs syndrome, as it does not appear in any current evidence-based treatment guidelines and lacks supporting data for efficacy or safety in this condition. 1

Current Evidence-Based Treatment Algorithm

The American Academy of Sleep Medicine has established a clear treatment hierarchy for RLS that does not include ketamine:

First-Line Treatment

• Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line therapy with moderate certainty of evidence, due to their superior efficacy and lower risk of augmentation compared to dopaminergic agents. 1, 2
• Iron supplementation should be initiated if serum ferritin ≤75 ng/mL or transferrin saturation <20%, as correcting iron deficiency can significantly improve symptoms independent of other medications. 1

Second-Line Treatment for Refractory Cases

• Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended for moderate to severe RLS, particularly for refractory cases or when treating dopamine agonist-related augmentation. 1, 3
• Long-term observational studies demonstrate relatively low risks of abuse or overdose in appropriately screened RLS patients, with only small dose increases over 2-10 years. 1

Alternative Options

• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological alternative. 1
• Dipyridamole may be considered as a second-line pharmacological option with low certainty of evidence. 1

Why Ketamine Is Not Recommended

While one older review from 2006 mentioned ketamine among various agents studied for RLS 4, this finding has not been incorporated into any modern treatment guidelines. The American Academy of Sleep Medicine's comprehensive 2026 guidelines explicitly do not include ketamine in their treatment algorithm. 1

The absence of ketamine from current guidelines reflects:

• Lack of high-quality randomized controlled trials demonstrating efficacy
• No established dosing protocols for RLS
• Unclear safety profile for chronic use in this population
• Availability of multiple evidence-based alternatives with proven efficacy

Critical Clinical Approach

For patients who have failed first-line treatments:

1. Verify iron status has been adequately addressed (ferritin ≤75 ng/mL or transferrin saturation <20% warrants supplementation). 1

2. Ensure adequate dosing of alpha-2-delta ligands before declaring treatment failure (gabapentin up to 2400 mg/day, pregabalin with appropriate titration). 1

3. Consider opioid therapy (extended-release oxycodone, methadone, or buprenorphine) for truly refractory cases, with appropriate screening for misuse risk and monitoring for respiratory depression. 1, 3

4. Avoid dopamine agonists (pramipexole, ropinirole, rotigotine) due to high risk of augmentation—a paradoxical worsening of symptoms with long-term use. 1, 2

Important Caveats

• Patients requesting ketamine for RLS should be counseled about the lack of evidence and guided toward proven therapies. 1
• The mention of ketamine in older literature 4 predates modern understanding of RLS pathophysiology and the development of current evidence-based treatment algorithms.
• Experimental or off-guideline treatments should only be considered after exhausting all evidence-based options and in consultation with RLS specialists. 1