Is Pregabalin (Lyrica) Superior to Gabapentin for RLS?
Pregabalin and gabapentin are equally recommended as first-line treatments for RLS with identical strength of recommendation (strong) and certainty of evidence (moderate), meaning neither is considered superior in efficacy, though pregabalin offers practical dosing advantages. 1, 2
Guideline Recommendations Show Equivalence
The American Academy of Sleep Medicine places gabapentin, gabapentin enacarbil, and pregabalin in the same tier as first-line alpha-2-delta ligand therapy, all receiving strong recommendations with moderate certainty of evidence. 1, 2
No guideline differentiates these agents in terms of efficacy for RLS symptom control—they are presented as interchangeable options within the alpha-2-delta ligand class. 1, 2
The American College of Physicians similarly recommends alpha-2-delta ligands (gabapentin, pregabalin, or gabapentin enacarbil) as first-line treatment without distinguishing superiority among them. 3
Practical Advantages of Pregabalin
Pregabalin offers twice-daily dosing compared to gabapentin's three-times-daily requirement, which may improve adherence, particularly in elderly patients who struggle with complex dosing schedules. 1, 2, 3
Pregabalin has potentially superior bioavailability compared to regular gabapentin, though this has not translated into demonstrated clinical superiority in head-to-head RLS trials. 1, 2, 3
Gabapentin requires titration starting at 300 mg three times daily, increasing by 300 mg/day every 3-7 days to reach maintenance doses of 1800-2400 mg/day divided three times daily. 1, 2
Single nighttime dosing of gabapentin fails to address daytime RLS symptoms and provides suboptimal 24-hour coverage, making the three-times-daily regimen necessary. 1
Cost Considerations Favor Gabapentin
Regular gabapentin and pregabalin have negligible cost compared to gabapentin enacarbil, making them cost-effective alternatives. 1
In real-world practice, generic gabapentin is substantially less expensive than pregabalin, which may influence treatment selection when efficacy is equivalent. 1
Limited Direct Comparative Evidence
The 2003 study comparing gabapentin to ropinirole (a dopamine agonist) showed gabapentin efficacy but did not compare gabapentin to pregabalin. 4
A 2021 study evaluated pregabalin as add-on therapy to dopamine agonists, showing efficacy, but this does not establish superiority over gabapentin monotherapy. 5
No high-quality head-to-head trials directly comparing pregabalin to gabapentin for RLS exist in the current evidence base.
Common Side Effect Profile
Both agents share similar adverse effects including somnolence and dizziness, which are typically transient and mild. 1, 6, 7, 8
The American Academy of Sleep Medicine notes that alpha-2-delta ligands are preferred over dopamine agonists precisely because they avoid augmentation—a paradoxical worsening of symptoms seen with long-term dopamine agonist use. 1, 2
Clinical Decision Algorithm
Start with regular gabapentin (300 mg three times daily, titrating to 1800-2400 mg/day) as the most cost-effective first-line option. 1, 2
If adherence issues arise with three-times-daily dosing, particularly in elderly patients or those with complex medication regimens, switch to pregabalin with twice-daily dosing. 2, 3
If cost is not a barrier and patient preference favors simpler dosing from the outset, pregabalin is a reasonable initial choice given equivalent efficacy. 1, 2
Always check morning fasting ferritin and transferrin saturation before initiating either medication, supplementing with iron if ferritin ≤75 ng/mL or transferrin saturation <20%. 1, 2, 3
Critical Pitfalls to Avoid
Do not assume pregabalin is "stronger" or more effective—this is not supported by guidelines or evidence; the choice should be based on dosing convenience and cost. 1, 2
Avoid single nighttime dosing of gabapentin, as this provides inadequate 24-hour symptom coverage. 1
Monitor for misuse potential with alpha-2-delta ligands, as there is increasing evidence these agents may be misused in certain populations. 1
Recheck ferritin every 6-12 months, as brain iron deficiency may persist despite symptom improvement with either medication. 2, 3