Patient taking mirtazapine (Remeron) 7.5 mg nightly for insomnia with worsening restless legs syndrome and does not wish to discontinue mirtazapine; is it appropriate to increase ropinirole from 0.25 mg to 0.5 mg at bedtime?

Do Not Increase Ropinirole – Transition to First-Line Therapy Instead

You should not increase ropinirole from 0.25 mg to 0.5 mg because the American Academy of Sleep Medicine (2025) issues a conditional recommendation with moderate certainty of evidence against the standard use of ropinirole due to high augmentation risk—a paradoxical worsening of RLS symptoms that occurs with continued dopamine agonist therapy. 1, 2

Why Increasing Ropinirole Is Contraindicated

• Augmentation risk is substantial with ropinirole, presenting as earlier-day symptom onset (afternoon instead of evening), increased intensity, and spread to arms or trunk—exactly what your patient may already be experiencing with worsening restless legs. 1, 3

• Mirtazapine at 7.5 mg is likely exacerbating the RLS because the American Academy of Sleep Medicine explicitly recommends addressing serotonergic medications as potential exacerbating factors for RLS. 1 However, since the patient refuses to discontinue mirtazapine, you must optimize RLS treatment with evidence-based first-line agents rather than escalating a medication that carries high augmentation risk.

• The current worsening of symptoms may represent early augmentation from the 0.25 mg ropinirole dose, not inadequate dosing—increasing the dose will worsen this phenomenon over time. 1, 3, 4

Evidence-Based Management Algorithm

Step 1: Check Iron Status Immediately

• Obtain morning fasting serum ferritin and transferrin saturation after avoiding iron supplements for ≥24 hours. 1
• Supplement if ferritin ≤75 ng/mL or transferrin saturation <20% with oral ferrous sulfate (conditional recommendation, moderate certainty) or IV ferric carboxymaltose (strong recommendation, moderate certainty) for faster repletion. 1
• Iron deficiency exacerbates RLS independent of medication effects and may be contributing to apparent treatment failure. 1

Step 2: Initiate Alpha-2-Delta Ligand (First-Line Therapy)

• Start gabapentin 300 mg three times daily (strong recommendation, moderate certainty of evidence from the American Academy of Sleep Medicine). 1
• Titrate by 300 mg/day every 3–7 days to a target maintenance dose of 1800–2400 mg/day divided three times daily; maximum studied dose is 3600 mg/day. 1
• Alternative: pregabalin allows twice-daily dosing with superior bioavailability compared to regular gabapentin (strong recommendation, moderate certainty). 1

Step 3: Taper Ropinirole Once Gabapentin Reaches Therapeutic Dose

• Do not abruptly stop ropinirole—begin gradual taper only after gabapentin has been titrated to at least 1200–1800 mg/day and symptoms are controlled. 5
• Reduce ropinirole by 0.25 mg every 3–7 days while monitoring for breakthrough symptoms. 5
• Warn the patient that temporary symptom worsening during the transition is expected but will resolve as the alpha-2-delta ligand takes full effect. 5

Step 4: Manage Breakthrough Symptoms During Transition

• If severe breakthrough symptoms occur during the taper, increase the gabapentin dose more rapidly (up to 2400–3600 mg/day) rather than increasing or maintaining ropinirole. 1, 5
• For refractory breakthrough symptoms unresponsive to gabapentin dose adjustments, extended-release oxycodone can be used temporarily (conditional recommendation, moderate certainty), but screen for untreated obstructive sleep apnea first due to respiratory depression risk. 1, 5

Critical Pitfalls to Avoid

• Never increase ropinirole dose in response to worsening symptoms—this creates a vicious cycle of progressive augmentation requiring ever-higher doses with paradoxically worse symptoms. 1, 5, 3

• Do not switch to another dopamine agonist (pramipexole, rotigotine)—these carry identical augmentation risk, with one study showing 50% of patients who switched to rotigotine discontinued within one year due to lack of efficacy or side effects. 1, 5

• Avoid using levodopa as a bridge medication—it has an even higher augmentation rate than ropinirole. 1, 5

• Do not use clonazepam as monotherapy—the American Academy of Sleep Medicine explicitly recommends against clonazepam for RLS (conditional recommendation, very low certainty) because it only improves subjective sleep quality without reducing objective RLS markers. 1

Addressing the Mirtazapine Issue

• Mirtazapine's serotonergic effects are worsening the RLS, but since the patient refuses discontinuation, you must compensate with aggressive first-line RLS therapy. 1

• Consider discussing a trial period off mirtazapine once RLS is optimally controlled with gabapentin/pregabalin and iron supplementation—the patient may find that improved RLS control eliminates the need for mirtazapine for insomnia. 1

• If mirtazapine must be continued, ensure gabapentin is titrated to the higher end of the dosing range (2400–3600 mg/day) to overcome the serotonergic exacerbation. 1

Monitoring and Follow-Up

• Recheck ferritin every 6–12 months because brain iron deficiency may persist despite symptom improvement. 1, 5

• Monitor for gabapentin side effects (somnolence, dizziness), which are typically transient and mild. 1

• Assess for improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) at 2–4 week intervals during titration. 1