Pregabalin for Restless Legs Syndrome
Pregabalin is highly effective for treating RLS and is strongly recommended by the American Academy of Sleep Medicine as first-line therapy, with superior efficacy compared to placebo and significantly lower augmentation rates compared to dopamine agonists like pramipexole. 1
First-Line Treatment Status
The American Academy of Sleep Medicine strongly recommends pregabalin as first-line pharmacological treatment for RLS (strong recommendation, moderate certainty of evidence), alongside other alpha-2-delta ligands like gabapentin and gabapentin enacarbil. 1
This recommendation prioritizes pregabalin over dopamine agonists (pramipexole, ropinirole, rotigotine) due to the high risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread—that occurs with long-term dopaminergic therapy. 1, 2
Evidence of Efficacy
In a landmark 52-week randomized controlled trial, pregabalin 300 mg daily demonstrated a 4.5-point greater improvement in International RLS Study Group Rating Scale scores compared to placebo (P<0.001), with 71.4% of patients achieving "very much improved" or "much improved" status versus 46.8% with placebo. 3
The same trial showed pregabalin had a significantly lower augmentation rate (2.1%) compared to pramipexole 0.5 mg (7.7%, P=0.001) over 40-52 weeks of treatment. 3
Dose-response studies demonstrate that pregabalin's effect is dose-dependent, with 90% of maximal efficacy achieved at approximately 124 mg/day, though clinical trials typically use 150-600 mg daily doses. 4
Dosing Strategy
Start pregabalin at 75-150 mg at bedtime and titrate upward based on symptom response. 5, 6
Effective doses typically range from 150-450 mg daily, with most patients responding to 300 mg daily. 3, 6
Pregabalin allows for twice-daily dosing and may have superior bioavailability compared to gabapentin, which requires three-times-daily dosing for optimal effect. 1
Safety Profile and Monitoring
The most common adverse effects are dizziness and somnolence, which are typically dose-related and transient. 6, 4
Critical safety consideration: In the 52-week trial, there were six cases of suicidal ideation in the pregabalin group, requiring monitoring for mood changes and suicidal thoughts. 3
Monitor for potential misuse, as there is increasing evidence that alpha-2-delta ligands may be misused in certain populations. 1
Exercise caution in patients with untreated obstructive sleep apnea or chronic obstructive pulmonary disease due to risk of respiratory depression. 1
Treatment Algorithm Before Starting Pregabalin
Always check serum ferritin and transferrin saturation first (ideally morning fasting, after avoiding iron supplements for 24 hours), and supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20%. 1
Address exacerbating factors including alcohol, caffeine, antihistamines, serotonergic medications, antidopaminergic medications, and untreated sleep apnea. 1
Iron supplementation alone can significantly improve RLS symptoms independent of pregabalin therapy. 1
Special Clinical Scenarios
Pregabalin is particularly effective as add-on therapy in patients already taking dopamine agonists but experiencing persistent symptoms, side effects, or comorbid insomnia, with significant improvements in both RLS symptoms (P<0.001) and insomnia severity (P=0.036). 5
For patients with RLS complicated by neuropathic pain, pregabalin offers dual benefit by addressing both conditions simultaneously, with 84% of patients maintaining therapy at a mean dose of 305 mg daily. 7
In end-stage renal disease, gabapentin is preferred over pregabalin due to lower risk of altered mental status and falls (pregabalin carries 50-68% higher hazard versus 31-41% for gabapentin). 1
Advantages Over Dopamine Agonists
Pregabalin avoids the augmentation phenomenon that plagues long-term dopamine agonist therapy, making it superior for sustained symptom control. 1, 3
Unlike pramipexole and ropinirole, pregabalin does not cause impulse control disorders (compulsive gambling, shopping, eating, or sexual behaviors). 2
Symptom improvement begins at week 1 and continues to increase through week 6 and beyond, with sustained efficacy demonstrated through 52 weeks. 4, 3
Critical Pitfalls to Avoid
Do not use pregabalin as monotherapy without first assessing and correcting iron deficiency, as this represents a reversible cause of RLS that should be addressed first. 1
Do not assume lower doses are adequate—while 90% efficacy occurs at 124 mg/day in dose-response models, clinical practice typically requires 300 mg daily for optimal symptom control. 4, 3
Do not overlook medication-induced RLS worsening from antipsychotics, SSRIs, or antihistamines, which should be discontinued or switched before escalating pregabalin doses. 1