Why do approximately 25‑30% of patients with restless‑legs syndrome treated with gabapentinoids such as gabapentin or gabapentin enacarbil lose therapeutic benefit after a few years?

Why Gabapentinoids May Stop Working After a Few Years in RLS Patients

The 25-30% loss of therapeutic benefit with gabapentinoids after a few years is not due to true pharmacological tolerance or "augmentation" (which is specific to dopamine agonists), but rather reflects the natural progression of RLS disease severity, inadequate dosing, development of comorbidities that worsen RLS, or declining iron stores over time.

Understanding the Phenomenon

The question references a specific percentage (25-30%) that does not appear in current high-quality RLS guidelines or research. However, treatment failure with gabapentinoids does occur and differs fundamentally from the well-documented augmentation phenomenon seen with dopamine agonists 1, 2.

Key Distinction from Dopamine Agonist Augmentation

• Gabapentinoids do NOT cause augmentation, the iatrogenic worsening characterized by earlier symptom onset, increased intensity, and anatomic spread that occurs with dopamine agonists at an annual incidence of 7-10% 1, 2.
• This is precisely why the American Academy of Sleep Medicine now strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, pregabalin) as first-line therapy with moderate certainty of evidence 1.

Primary Reasons for Apparent Treatment Failure

1. Progressive Disease Severity

• RLS is a chronic, often progressive neurological disorder that naturally worsens over time in many patients, independent of treatment 2.
• The underlying pathophysiology—involving brain iron deficiency and dopaminergic dysfunction—may advance despite stable medication dosing 2.

2. Inadequate Initial or Maintenance Dosing

• Many patients receive subtherapeutic doses of gabapentinoids 1.
• For gabapentin: the recommended maintenance dose is 1800-2400 mg/day divided three times daily, with maximum studied doses up to 3600 mg/day 1.
• The FDA-approved 600 mg once-daily dose of gabapentin enacarbil may provide insufficient coverage for patients with severe symptoms or sleep disturbance, as studies show 1200 mg/day is more effective for both subjective RLS symptoms and associated sleep problems 3.
• Common pitfall: Clinicians often fail to titrate to adequate doses, leaving patients undertreated 1.

3. Declining Iron Stores

• Iron deficiency is a fundamental driver of RLS pathophysiology 1, 2.
• The American Academy of Sleep Medicine recommends supplementation when ferritin ≤75 ng/mL or transferrin saturation <20%—thresholds higher than general population guidelines because brain iron deficiency can persist despite normal serum parameters 1.
• Critical monitoring gap: Iron studies should be reassessed every 6-12 months, but this is frequently neglected in clinical practice 1.
• Even patients who initially respond to gabapentinoids may experience symptom recurrence if iron stores decline over time 1.

4. Development or Worsening of Comorbid Conditions

• RLS commonly coexists with conditions that independently worsen symptoms 2:
  • End-stage kidney disease (24% prevalence) 2
  • Peripheral neuropathy (21.5% prevalence) 2
  • Cardiovascular disease (29.6% prevalence) 2
  • Depression (30.4% prevalence) 2
• As these conditions progress, RLS symptoms may worsen despite stable gabapentinoid therapy 2.

5. Introduction of RLS-Exacerbating Medications

• The American Academy of Sleep Medicine recommends addressing potential exacerbating factors including serotonergic antidepressants, antidopaminergic medications, and centrally acting H1 antihistamines 1, 2.
• Patients may be prescribed these medications for other conditions over time, inadvertently worsening their RLS 1.

6. Untreated or Worsening Sleep Apnea

• Obstructive sleep apnea is an independent exacerbating factor for RLS 1.
• Sleep apnea may develop or worsen over years, contributing to apparent gabapentinoid treatment failure 1.

Algorithmic Approach When Gabapentinoids "Stop Working"

Step 1: Verify Adequate Dosing

• Confirm the patient is receiving therapeutic doses 1:
  • Gabapentin: 1800-2400 mg/day divided TID (not single nighttime dosing) 1
  • Gabapentin enacarbil: Consider 1200 mg once daily rather than 600 mg for severe symptoms 3
  • Pregabalin: 300-600 mg/day divided BID 1

Step 2: Reassess Iron Status

• Obtain morning fasting ferritin and transferrin saturation after ≥24-hour iron-free interval 1.
• Supplement if ferritin ≤75 ng/mL or transferrin saturation <20% 1.
• Consider IV ferric carboxymaltose (750-1000 mg) for rapid correction if oral iron fails or is not tolerated 1.

Step 3: Review Medication List

• Discontinue or substitute RLS-exacerbating medications 1, 2:
  • Serotonergic antidepressants
  • Dopamine antagonists (antipsychotics, metoclopramide)
  • Centrally acting antihistamines (diphenhydramine)

Step 4: Screen for and Treat Comorbidities

• Evaluate for untreated obstructive sleep apnea 1.
• Assess for progression of peripheral neuropathy, kidney disease, or cardiovascular conditions 2.

Step 5: Consider Combination or Alternative Therapy

• If gabapentinoid optimization and iron repletion fail, the American Academy of Sleep Medicine conditionally recommends extended-release oxycodone or other low-dose opioids (methadone 5-10 mg daily, buprenorphine) for refractory cases 1, 2, 4.
• Long-term studies show relatively low risks of abuse/overdose in appropriately screened RLS patients, with only small dose increases over 2-10 years 1.

Critical Pitfalls to Avoid

• Do not assume "tolerance" to gabapentinoids without first optimizing dose, checking iron status, and reviewing for exacerbating factors 1.
• Do not switch to dopamine agonists (pramipexole, ropinirole, rotigotine) as they carry a 7-10% annual augmentation risk and are no longer recommended as first-line therapy 1, 2.
• Do not use single nighttime gabapentin dosing for patients with daytime symptoms or severe disease—divided dosing provides superior 24-hour coverage 1.
• Do not neglect ongoing iron monitoring—even patients with initial normal ferritin may develop deficiency over time 1.

Evidence Quality and Nuances

The most recent and highest-quality evidence comes from the 2025 American Academy of Sleep Medicine guidelines 1, which supersede older recommendations that favored dopamine agonists 5, 6. The shift to gabapentinoids as first-line therapy is based on their superior long-term safety profile and absence of augmentation risk 1, 2.

While the specific "25-30%" figure cited in the question lacks direct evidence support, treatment failure with gabapentinoids is a recognized clinical phenomenon that differs fundamentally from dopamine agonist augmentation and is typically addressable through systematic evaluation and optimization 1, 4.