The First-Line RLS Drug Changed. Not Every Patient’s Chart Has Caught Up.
A resident reaches for the drug that was first-line for two decades. The attending stops her — not because the drug fails to work, but because it works today at the cost of a problem that tends to arrive later.
Y.P., a 55-year-old woman, has worked as an accountant for nearly thirty years, the last twelve running her own small practice out of a converted spare room, work that keeps her sitting for long stretches especially during the January-through-April tax season. She was referred to the sleep clinic by her primary care physician for new-onset, moderate-to-severe restless legs syndrome that developed gradually over the past year — uncomfortable, hard-to-describe sensations deep in both legs, now occurring most evenings and significantly delaying her ability to fall asleep. She initially attributed it to the long hours at her desk during tax season, a reasonable enough guess given her work, but the pattern persisted clearly even through the slower months and on weekends when she wasn’t sitting nearly as much.
Her ferritin, checked at referral, came back at 42 ng/mL — below the RLS-specific treatment threshold her sleep physician later explained to her, though well within what her primary care physician’s lab report had flagged as a normal general range. Iron repletion was started three months ago and she has taken it consistently, by her own account and her pharmacy’s refill records, without adequate symptom improvement in that time.
She has no other major medical conditions, takes no medications known to worsen RLS, and is being seen today by a sleep medicine fellow, working under her attending’s supervision, who has proposed starting pramipexole — the agent she trained on as first-line during the earlier stages of her fellowship and the one most familiar to her from the literature she read during residency several years ago.
Supervision visit, choosing a first pharmacologic agent
Pramipexole has strong, well-established efficacy data for RLS, and it’s genuinely what I trained on as the standard first-line agent — rapid, often dramatic symptom relief, and a long track record. Her iron repletion hasn’t been enough on its own, so I think starting a dopamine agonist now is the natural next step.
You’re right that pramipexole works, often quickly and well — that was never really in question, and it’s exactly why it held first-line status for so long. But the standard changed for a specific, evidence-based reason, not because efficacy turned out to be overstated: augmentation, the paradoxical worsening of RLS symptoms with long-term dopaminergic use, occurs in a meaningful proportion of patients over time, and once it develops it is genuinely difficult to manage, often requiring a slow, uncomfortable cross-taper off the very drug that helped initially.
The 2025 AASM guideline reflects that trade-off directly, moving alpha-2-delta ligands like gabapentin enacarbil to first-line status for most adults specifically to avoid starting patients on a path with a real, well-documented long-term liability when a comparably effective alternative without that specific risk exists. For a treatment-naive patient like her, with no compelling reason to prefer the dopamine agonist specifically, I’d start there instead.
Agreed: gabapentin enacarbil started as first-line, iron repletion continued in parallel, and pramipexole held in reserve rather than started — with the fellow noting explicitly, for her own ongoing training, that the guideline had moved since she first learned the standard approach.
No real disagreement remained once the augmentation trade-off was explained — the fellow’s initial position wasn’t wrong about pramipexole’s efficacy, and the physician’s response conceded that directly before explaining why efficacy alone no longer settles the first-line question.