What is the role of Dipyridamole in treating Restless Leg Syndrome (RLS)?

Dipyridamole for Restless Leg Syndrome (RLS)

Dipyridamole is recommended as a treatment option for adults with Restless Leg Syndrome, with evidence showing clinically significant improvement in disease severity with moderate effect size. 1

Evidence-Based Treatment Algorithm for RLS

First-Line Treatments (Strong Recommendations)

1. Alpha-2-delta ligands:

   • Gabapentin enacarbil
   • Gabapentin
   • Pregabalin

2. Iron supplementation (when appropriate):

   • IV ferric carboxymaltose (if ferritin ≤75 ng/mL or transferrin saturation <20%)

Second-Line Treatments (Conditional Recommendations)

1. Dipyridamole (conditional recommendation, low certainty of evidence)
2. Oral iron (ferrous sulfate) (if ferritin ≤75 ng/mL or transferrin saturation <20%)
3. Other IV iron formulations (low molecular weight iron dextran, ferumoxytol)
4. Extended-release oxycodone and other opioids
5. Bilateral high-frequency peroneal nerve stimulation

Dipyridamole's Role in RLS Treatment

Dipyridamole has emerged as a promising non-dopaminergic treatment option for RLS. According to the 2025 American Academy of Sleep Medicine (AASM) clinical practice guideline, dipyridamole is suggested over no dipyridamole for adults with RLS (conditional recommendation, low certainty of evidence) 1.

Mechanism of Action

Dipyridamole works through adenosinergic mechanisms. RLS may be associated with a hypoadenosinergic state, particularly in patients with brain iron deficiency. As an inhibitor of equilibrative nucleoside transporters (ENT1/ENT2), dipyridamole increases extracellular adenosine levels, which may help alleviate RLS symptoms 2, 3.

Efficacy

Clinical evidence demonstrates:

• Significant improvement in RLS severity as measured by the International Restless Legs Rating Scale (IRLS) 2
• Reduction in periodic leg movement index during sleep 2, 3
• Improvement in both sensory and motor symptoms 3

In a randomized, placebo-controlled crossover study, IRLS scores improved from a mean of 24.1 at baseline to 11.1 after two weeks of dipyridamole treatment, compared to 18.7 with placebo (p<0.001) 2.

Dosing

The mean effective dose of dipyridamole in clinical studies was approximately 218-282 mg/day 2, 3.

Side Effects

Common side effects include:

• Abdominal distension (18%)
• Dizziness (10.7%)
• Diarrhea (7.1%)
• Asthenia (7.1%)

These side effects are generally mild, and the overall undesirable effect size is deemed small 1.

Important Clinical Considerations

Before Starting Treatment

1. Address exacerbating factors:

   • Alcohol and caffeine consumption
   • Medications (antihistamines, serotonergic agents, antidopaminergic drugs)
   • Untreated obstructive sleep apnea

2. Check iron status:

   • Morning serum ferritin and transferrin saturation (avoid iron supplements for 24 hours prior)
   • Consider iron supplementation if ferritin ≤75 ng/mL or transferrin saturation <20%

Treatment Selection Considerations

• Dipyridamole offers an alternative to dopaminergic agents, which have fallen out of favor as first-line treatments due to the risk of augmentation 4
• Cost of dipyridamole is considered negligible, and it does not negatively impact health equity 1
• The intervention is feasible to implement in most clinical settings 1

Monitoring and Follow-up

• Regular assessment of symptom severity using validated tools (IRLS)
• Monitoring for side effects
• Periodic reassessment of iron status

Caveats and Pitfalls

1. Limited evidence base: The recommendation for dipyridamole is based on low certainty evidence 1

2. Not FDA-approved for RLS: While included in clinical guidelines, dipyridamole is not specifically FDA-approved for RLS treatment

3. Potential drug interactions: As a platelet inhibitor, dipyridamole may increase bleeding risk when combined with anticoagulants or antiplatelet drugs

4. Avoid in specific populations: Use with caution in patients with hypotension, coronary artery disease, or valvular heart disease

The emergence of dipyridamole as a treatment option represents a shift toward targeting non-dopaminergic mechanisms in RLS, potentially avoiding the augmentation issues associated with dopamine agonists while providing effective symptom relief 5, 6.