In a patient with restless‑legs syndrome treated with pregabalin and pramipexole 0.375 mg (reduced from 0.75 mg), will symptoms continue to augment while pramipexole is continued?

Risk of Continued Augmentation on Pramipexole

Yes, symptoms will almost certainly continue to augment as long as pramipexole is continued, even at the reduced dose of 0.375 mg. The American Academy of Sleep Medicine now explicitly recommends against the standard use of pramipexole due to this augmentation risk, with moderate certainty of evidence. 1

Understanding Augmentation Risk

• Augmentation is a progressive, iatrogenic worsening that occurs in approximately 33% of patients on pramipexole, with most cases developing within the first year and all by 30 months of treatment. 2
• The phenomenon manifests as earlier daily symptom onset (afternoon instead of evening), increased intensity, and anatomic spread to arms or trunk—this is a paradoxical worsening despite medication use. 1, 3
• Dose reduction does not eliminate augmentation risk; it merely delays the inevitable progression, as the underlying mechanism is related to chronic dopaminergic stimulation rather than dose alone. 3, 4
• Even at lower doses like 0.375 mg, the augmentation process continues because the pathophysiology involves dopamine receptor sensitization that persists with any ongoing dopamine agonist exposure. 4

Current Guideline-Based Recommendation

• The 2025 American Academy of Sleep Medicine guidelines represent a major paradigm shift: pramipexole is no longer recommended as standard therapy and should be discontinued in favor of alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line treatment. 1
• This patient is already on pregabalin, which is the appropriate first-line agent—the critical next step is to completely discontinue pramipexole rather than maintain it at any dose. 1, 3

Evidence Supporting Complete Discontinuation

• A landmark 52-week randomized trial demonstrated that pregabalin had a significantly lower augmentation rate (2.1%) compared to pramipexole 0.5 mg (7.7%, P=0.001), and pregabalin provided superior long-term symptom control without the augmentation phenomenon. 5
• Continuing pramipexole alongside pregabalin defeats the purpose of switching to an alpha-2-delta ligand, as the dopamine agonist will continue driving augmentation regardless of pregabalin coverage. 3, 4

Practical Discontinuation Strategy

• Optimize pregabalin dosing first before tapering pramipexole: ensure the patient is on an adequate dose (typically 300–600 mg/day divided twice daily) to provide symptom coverage during the transition. 1, 3
• Check iron status immediately: supplement if ferritin ≤75 ng/mL or transferrin saturation <20%, as correcting iron deficiency significantly improves RLS symptoms and facilitates dopamine agonist withdrawal. 1, 3
• Taper pramipexole very slowly (reduce by 0.125 mg every 1–2 weeks) to minimize rebound RLS and insomnia, which can be profound even with small dose reductions. 3, 4
• Expect temporary symptom worsening during the taper—this is rebound RLS, not treatment failure—and resist the urge to increase pramipexole or add another dopamine agonist. 3
• For severe breakthrough symptoms unresponsive to pregabalin dose adjustments, consider temporary use of extended-release oxycodone to facilitate the transition, but screen for untreated obstructive sleep apnea first. 3

Critical Pitfalls to Avoid

• Do not simply reduce pramipexole and maintain it indefinitely at a lower dose—this perpetuates augmentation risk and contradicts current evidence-based guidelines. 1, 3
• Do not switch to another dopamine agonist (ropinirole, rotigotine) thinking it will be safer—all dopamine agonists carry the same augmentation risk. 1, 6
• Do not increase pramipexole dose in response to worsening symptoms—this creates a vicious cycle of escalating augmentation requiring progressively higher doses. 3, 6
• Do not use levodopa as a bridge medication—it has an even higher augmentation rate than pramipexole. 3

Long-Term Outcome

• Patients who successfully transition from pramipexole to pregabalin monotherapy experience sustained symptom control without augmentation, as alpha-2-delta ligands do not carry the paradoxical worsening phenomenon seen with dopaminergic agents. 1, 3, 5
• The goal is complete pramipexole discontinuation within 2–3 months, with pregabalin (and corrected iron status) providing durable long-term RLS management. 3, 4