Endep (Amitriptyline) Should NOT Be Used for Restless Legs Syndrome
Amitriptyline (Endep) is contraindicated for restless legs syndrome and will likely worsen your symptoms—avoid it entirely. 1
Why Amitriptyline Worsens RLS
Tricyclic antidepressants like amitriptyline are specifically identified as medications that exacerbate RLS symptoms through their antihistaminergic and serotonergic properties. 1
The American Academy of Sleep Medicine explicitly recommends addressing and eliminating potential exacerbating factors, including serotonergic medications and antihistaminergic medications, before considering any pharmacologic treatment for RLS. 1
Multiple medication classes have been reported to trigger or worsen RLS, and tricyclic antidepressants are prominently listed among these culprits alongside SSRIs, lithium, and dopamine antagonists. 1
What You Should Use Instead: Evidence-Based First-Line Treatment
The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line therapy for RLS, with strong recommendation and moderate certainty of evidence. 1
Before starting any medication, check morning fasting serum ferritin and transferrin saturation (after avoiding iron supplements for ≥24 hours), and supplement iron if ferritin ≤75 ng/mL or transferrin saturation <20%. 1
Practical Treatment Algorithm
Step 1: Eliminate exacerbating factors
- Stop all antihistamines, serotonergic medications (including amitriptyline), antidopaminergic agents, alcohol, and caffeine—especially in the evening. 1
- Screen for and treat obstructive sleep apnea if present. 1
Step 2: Assess and correct iron status
- Obtain morning fasting ferritin and transferrin saturation. 1
- If ferritin ≤75 ng/mL or transferrin saturation <20%, start oral ferrous sulfate or consider IV ferric carboxymaltose for rapid correction. 1
Step 3: Initiate first-line pharmacologic therapy
- Start gabapentin 300 mg three times daily, then increase 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 3600 mg/day). 1
- Alternatively, pregabalin allows twice-daily dosing and has superior bioavailability compared to regular gabapentin. 1
- Gabapentin enacarbil is another strongly recommended option with moderate certainty of evidence. 1
Critical Pitfall to Avoid
Never use dopamine agonists (pramipexole, ropinirole, rotigotine) as first-line therapy due to high risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread occurring in 7–10% of patients annually. 1, 2
Do not assume that medications prescribed for sleep or mood disorders are safe in RLS—many antidepressants, including amitriptyline, will make your condition significantly worse. 1
Monitoring and Follow-Up
Reassess iron studies every 6–12 months, even after symptom resolution, as brain iron deficiency may persist despite normal serum parameters. 1
Monitor for side effects of alpha-2-delta ligands, particularly dizziness and somnolence, which are typically transient and mild. 1
Evaluate improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood). 1