A woman with chronic lymphedema started pramipexole 0.25 mg for restless‑legs syndrome and within 48 hours experienced markedly worsened symptoms; can this represent augmentation and how should it be managed?

Rapid Symptom Worsening with Pramipexole in RLS

This is NOT augmentation—augmentation cannot occur within 48 hours, and this patient requires immediate discontinuation of pramipexole with evaluation for alternative causes of symptom worsening.

Understanding the Timeline

Augmentation is a well-recognized complication of dopaminergic therapy for RLS, but it develops over weeks to months, not days. 1 The American Academy of Sleep Medicine explicitly warns about augmentation as a long-term adverse effect that is the primary reason for suggesting against standard use of pramipexole in RLS. 1, 2 This phenomenon involves treatment-induced worsening characterized by earlier symptom onset in the day, increased intensity, and spread to other body parts—but these changes emerge gradually with chronic exposure. 2

Research demonstrates that pramipexole shows efficacy from the very first night of administration, with significant improvement in RLS symptoms within hours. 3 A study of treatment-naïve patients showed dramatic symptom reduction (VAS scores dropping from 7.4 to 1.3) after a single 0.25 mg dose on the first night. 3 This immediate positive response is the expected pattern, not worsening.

What This Actually Represents

The 48-hour worsening in this patient indicates either:

• Paradoxical reaction to the medication - Some patients experience atypical responses to dopaminergic agents, though this is uncommon 1
• Coincidental disease progression - RLS symptoms naturally fluctuate and can worsen independently of treatment
• Unrecognized comorbidity - The lymphedema itself or related vascular/inflammatory processes may be exacerbating RLS symptoms
• Incorrect diagnosis - The symptoms may not be RLS but rather pain or discomfort from the lymphedema being misattributed

Immediate Management Steps

Stop pramipexole immediately. 1 Given the rapid symptom worsening and the fact that this represents an atypical response rather than expected augmentation, continuing the medication serves no purpose and may cause additional harm.

Reassess the diagnosis. Ensure this truly represents RLS and not lymphedema-related discomfort, peripheral neuropathy, or vascular claudication that mimics RLS symptoms.

Check iron studies. Measure ferritin and transferrin saturation, as iron deficiency is a reversible cause of RLS that should be addressed before pursuing other pharmacologic options. 1

Alternative Treatment Options

The 2025 American Academy of Sleep Medicine guidelines now recommend AGAINST standard use of pramipexole and other dopamine agonists for RLS due to augmentation risk with long-term use. 1 First-line alternatives include:

• Gabapentin or pregabalin - These are now preferred over dopamine agonists for long-term RLS management 1
• Iron supplementation - If ferritin <75 ng/mL or transferrin saturation <20%, iron therapy should be initiated 1
• Alpha-2-delta ligands - Gabapentin enacarbil is specifically FDA-approved for RLS and avoids augmentation risk 1

Dopamine agonists like pramipexole should only be considered in patients who explicitly prioritize short-term symptom relief over long-term safety and are willing to accept augmentation risk. 1, 2 This patient's immediate negative response makes her a particularly poor candidate for continued dopaminergic therapy.

Critical Pitfall to Avoid

Do not increase the pramipexole dose thinking higher doses will overcome the worsening symptoms. This patient's atypical response pattern suggests she is not a suitable candidate for this medication class. 1 The dose of 0.25 mg is already within the therapeutic range that shows efficacy in clinical trials. 3, 4