The use of Dipyridamole in the restless legs syndrome

Dipyridamole is the new kid on the block. A couple of recent studies have shown very encouraging findings for its use in treating RLS.

Dipyridamole is an interesting non-dopaminergic treatment for restless legs syndrome (RLS). It is not yet one of the main first-line drugs, but the evidence is promising enough that the latest American Academy of Sleep Medicine (AASM) guideline gives it a conditional recommendation for adults with RLS, albeit based on low certainty of evidence. Dipyridamole is better known as an antiplatelet medication, used in cardiovascular and stroke medicine. Its relevance to RLS comes from something quite different: adenosine. Adenosine (see adenosine on the Neurobiological influences page) is a neuromodulator that accumulates in the brain during wakefulness and contributes to sleep pressure and reduced neuronal excitability. One particularly important receptor is the adenosine A1 receptor (A1R). Activation of A1 receptors generally puts a brake on neuronal activity, including glutamate and dopamine signalling. It is thought that the model below explains the mechanism of action of Dipyridamole by increasing adenosine signalling.

Figure 1: Model of adenosine leading to RLS

Dipyridamole inhibits the ENT1/ENT2 nucleoside transporters, which can increase extracellular adenosine. In simplified terms, it may help restore some of the deficient adenosine signalling thought to occur in RLS.

A few studies have shown that Dipyridamole performs significantly and substantially better than placebo at relieving RLS symptoms. The difficulty with published studies on Dipyridamole is small sample sizes and no long-term followup. So although all indications for Dipyridamole use are promising more research is needed.

Once the firstline therapy dopamine agonists have now been relegated to the second tier of treatment for RLS primarily due to the potential for augmentation (RLS symptoms actually getting worse). Dipyridamole therefore attracts particular interest because it works through a completely different mechanism and isn't expected to produce dopaminergic augmentation.

There are some circumstances where there is a contraindication (Box 1) or at least precautions when considering dipyridamole as an RLS treatment.

Severe coronary artery disease, including unstable angina or a recent myocardial infarction. Dipyridamole is a vasodilator and can potentially aggravate myocardial ischaemia.
Low blood pressure or haemodynamic instability, including decompensated heart failure.
Left ventricular outflow obstruction, such as significant aortic stenosis.
Bleeding or coagulation disorders, because dipyridamole inhibits platelet function.
Myasthenia gravis, because changes in dipyridamole dosage can necessitate adjustment of myasthenia treatment.

Box 1: Dipyridamole contraindications

Dipyridamole dosing

For RLS, there isn't yet a universally established dipyridamole dosing guideline comparable with established RLS medicines. The best dosing information comes from the clinical trials, and treatment should be supervised by a doctor.

The main RLS randomized controlled trial used the following dose schedule:

Days 1–3: 100 mg/day
Then: increase to 200 mg/day
Second week: increase to 300 mg/day if clinically necessary
The mean effective dose was about 218 mg/day, and 18% of participants required 300 mg/day.

The timing of dosing of dipyridamole in the published RLS studies was 8PM to 9PM. Immediate release oral dipyridamole is absorbed fairly rapidly. Depending on the pharmacokinetic study, peak blood concentrations occur approximately 75-minutes to 150-minutes after a dose. There is one particularly important caveat. The controlled trial selected patients whose symptoms did not significantly begin before 7PM. Therefore, we cannot assume that a 9PM dose would be optimal for somebody whose RLS regularly begins in the late afternoon.

The NHS advice is to take conventional dipyridamole tablets before meals. The Mayo Clinic describes taking conventional dipyridamole with water at least 1-hour before or 2-hours after meals for optimal absorption.

Because dipyridamole affects platelet function and can cause dizziness or lower blood pressure, the appropriate dose also depends on other medications and medical conditions.

Side effects of Dipyridamole

In the small studies conducted on the efficacy of Dipyridamole in RLS reported side effects are in Box 2.

Abdominal bloating/distension
Dizziness
Diarrhoea
Asthenia (weakness/fatigue)
Flushing

Box 2: Dipyridamole side effects (RLS research studies)

Dipyridamole has been used for many years for cardiovascular indications, where other recognised side effects are included in Box 3.

Box 3: Dipyridamole side effects (long term use)

Headache
Nausea
Low blood pressure
Faintness
Increased bleeding tendency

For other treatment options see the pages:

Do not begin, stop or change an RLS medicine without advice from your doctor or pharmacist.

Last reviewed: 07/09/2026